molecular distinction between physiological and pathological...

Pharmacology & Therapeutics 128 (2010) 191–227

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Pharmacology & Therapeutics

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Molecular distinction between physiological and pathological cardiac hypertrophy:Experimental findings and therapeutic strategies

Bianca C. Bernardo a, Kate L. Weeks a,b, Lynette Pretorius a,c, Julie R. McMullen a,⁎a Cardiac Hypertrophy Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Australiab Faculty of Medicine, Dentistry and Health Sciences, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australiac Faculty of Medicine, Nursing and Health Sciences, Department of Medicine (Alfred Hospital), Monash University, Melbourne, Australia

Abbreviations: 4E-BP1, 4E binding protein 1; ACE, AnAtrial natriuretic peptide; ARB, Angiotensin receptor blopeptide; ca, constitutively active; CaM, calmodulin; CaMCN, calcineurin; CoA, coenzyme A; CREB, cAMP respcardiomyopathy; dn, dominant negative; ECM, extracellueukaryotic initiation factor 4E; ER, estrogen receptor; EGATA, GATA protein binding; Gp, guanine nucleotide binkinase 3; HDAC, histone deacetylase; HIF, hypoxia-inducinsulin-like growth factor 1; IGF1R, insulin-like growth fsteatosis; KO, knockout; LIF, leukemia inhibitory factordehydrogenase; MCIP, mitogen-enriched calcineurin-inactivated protein kinase kinase; MEKK, mitogen activatedchain kinase; mTOR, mammalian target of rapamycin; NNFAT, nuclear factor of activated T cells; Ntg, non-transkinase C; PKD, protein kinase D; PLB, phospholamban; PLRab, member of RAS oncogene family; Raf1, member ospecies; RTK, receptor tyrosine kinase; S6K, ribosomal S6transcription; TAK, TGF-β activated kinase; Tg, transgeni⁎ Corresponding author. P.O. Box 6492 St Kilda Road

E-mail address: [email protected] (J.R

0163-7258/$ – see front matter © 2010 Elsevier Inc. Aldoi:10.1016/j.pharmthera.2010.04.005

a b s t r a c t
a r t i c l e i n f o
Keywords:Heart failurePhosphoinositide 3-kinaseInsulin-like growth factor 1Physiological cardiac hypertrophyPathological cardiac hypertrophyGender differencesTherapeutic applications

Cardiac hypertrophy can be defined as an increase in heart mass. Pathological cardiac hypertrophy (heartgrowth that occurs in settings of disease, e.g. hypertension) is a key risk factor for heart failure. Pathologicalhypertrophy is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. In contrast,physiological cardiac hypertrophy (heart growth that occurs in response to chronic exercise training, i.e. the‘athlete's heart’) is reversible and is characterized by normal cardiac morphology (i.e. no fibrosis orapoptosis) and normal or enhanced cardiac function. Given that there are clear functional, structural,metabolic and molecular differences between pathological and physiological hypertrophy, a key question incardiovascular medicine is whether mechanisms responsible for enhancing function of the athlete's heartcan be exploited to benefit patients with pathological hypertrophy and heart failure. This review summarizeskey experimental findings that have contributed to our understanding of pathological and physiologicalheart growth. In particular, we focus on signaling pathways that play a causal role in the development ofpathological and physiological hypertrophy. We discuss molecular mechanisms associated with features ofcardiac hypertrophy, including protein synthesis, sarcomeric organization, fibrosis, cell death and energymetabolism and provide a summary of profiling studies that have examined genes, microRNAs and proteinsthat are differentially expressed in models of pathological and physiological hypertrophy. How gender andsex hormones affect cardiac hypertrophy is also discussed. Finally, we explore how knowledge of molecularmechanisms underlying pathological and physiological hypertrophy may influence therapeutic strategies forthe treatment of cardiovascular disease and heart failure.

giotensin converting enzyme; ACEI, Angiotensin convertickers; ARK, Adrenergic receptor kinase; ARs, Adrenergic rK, calcium/calmodulin-dependent protein kinases; c-fos,onse element-binding protein; CT-1, cardiotrophin 1lar matrix; EGF, epidermal growth factor; EGFR, epidermRK, extracellular signal-regulated kinases; ETA, endotheliding proteins; GPCR, G protein-coupled receptor; Grb2,ible factor; HSF1, heat shock transcription factor 1; Hsp, hactor 1 receptor; IP3, inositol 1,4,5-trisphosphate; JAK, Jan; LVPW, left ventricular posterior wall; MAPK, mitogenteracting protein; mCPT-1, muscle-type carnitine palmitoprotein kinase kinase kinase; MHC, myosin heavy chain;ab1, NGF1A-binding protein; NADPH, nicotinamide adegenic; PDE, phosphodiesterase; PE, phenylephrine; PI3KC, phospholipase C; PPAR, peroxisome proliferation-activf RAS oncogene family; Ran, member of RAS oncogenekinase; SERCA, sarcoplasmic reticulum Ca2+-ATPase; Src; TGF, transforming growth factor; TNF, tumor necrosisCentral, Melbourne Victoria 8008, Australia. Tel.: +61 38. McMullen).

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© 2010 Elsevier Inc. All rights reserved.

ng enzyme inhibitors; Adr, adrenaline; Ang II, Angiotensin II; ANP,eceptors; AT1, Angiotensin type 1 receptor; BNP, B-type natriureticc-fos oncogene; c-jun, c-jun oncogene; c-myc, c-myc oncogene; Cn/; cTNT, cardiac troponin T; DAG, diacylglycerol; DCM, dilatedal growth factor receptor; eIF2, eukaryotic initiation factor 2; eIF4E,n type A receptor; ET-I, endothelin 1; FAK, focal adhesion kinase;growth factor receptor bound protein 2; GSK3, glycogen synthaseeat shock protein; HW/BW, heart weight/body weight ratio; IGF1,us kinase; JNK, c-Jun amino-terminal kinase; JVS, juvenile visceralactivated protein kinase; MCAD, medium chain acyl coenzyme Ayltransferase 1; MEF2, myocyte enhancer factor 2; MEK, mitogenmiRNAs, microRNAs; MLC, myosin light chain; MLCK, myosin lightnine dinucleotide phosphate; NE, noradrenaline, norepinephrine;, phosphoinositide 3-kinase; PKA, protein kinase A; PKC, proteinated receptors; pS6, phosphorylation of 40 S ribosomal S6 protein;family; Ras, Ras oncogene; Rho, rhodopsin; ROS, reactive oxygenc, Rous sarcoma oncogene; STAT, signal transducer and activator offactor; TR, thyroid hormone receptor; Ub, ubiquitin; WT, wildtype.5321194; fax: +61 385321100.

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192 B.C. Bernardo et al. / Pharmacology & Therapeutics 128 (2010) 191–227

Contents

Fig. 1. Cellular prmitogen-activate

1. Cardiac hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1922. Experimental and genetic mouse models utilized in the identification of

signaling pathways that mediate cardiac hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . 1923. Overview of signaling cascades/proteins implicated

in mediating physiological and pathological cardiac growth . . . . . . . . . . . . . . . . . . . . . . . 1924. Molecular mechanisms associated with structural features of pathological and physiological hypertrophy . . . 1935. Molecular mechanisms associated with differences in

energy metabolism in pathological and physiological hypertrophy . . . . . . . . . . . . . . . . . . . . 1936. Characteristic gene expression changes associated with pathological and physiological hypertrophy . . . . 1947. Gender differences in cardiac hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1948. Therapeutic strategies for the treatment of heart failure . . . . . . . . . . . . . . . . . . . . . . . . . 1949. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196217

1. Cardiac hypertrophy

1.1. Introduction and overview

Cardiac hypertrophy can broadly be defined as an increase in heartmass. Growth of the postnatal heart is closely matched to itsfunctional load (Zak, 1984). In response to an increase in load (e.g.pressure overload in a setting of hypertension), the heart must workharder than under normal conditions. To counterbalance the chronicincrease in wall stress the muscle cells within the heart enlargeleading to an increase in size andmass (Cooper, 1987; Sugden & Clerk,1998; Hunter & Chien, 1999). The increase in heart mass is largely dueto an increase in ventricular weight. In the subsequent sections we

ocesses involved in the development of cardiac hypertrophy. ECM: extrd protein kinase, PI3K: phosphoinositide 3-kinase, ROS: reactive oxygen s

have described cardiac hypertrophy at the cellular level, differenttypes of cardiac hypertrophy (pathological and physiological), themolecular mechanisms responsible for different forms of cardiachypertrophy, gender differences, and possible treatment strategiesbased on the distinct molecular mechanisms associated withphysiological and pathological cardiac hypertrophy.

1.2. Cardiac hypertrophy at the cellular level

The heart is composed of cardiac myocytes (muscle cells), non-myocytes (e.g. fibroblasts, endothelial cells, mast cells, vascular smoothmuscle cells), and the surrounding extracellularmatrix (Nag, 1980; Zak,1984). Ventricular cardiacmyocytesmake up only one-third of the total

acellular matrix, FAO: fatty acid oxidation, GPCR: G protein-coupled receptor, MAPK:pecies, SERCA: sarcoplasmic reticulum Ca2+ ATPase.

193B.C. Bernardo et al. / Pharmacology & Therapeutics 128 (2010) 191–227

cell number, but account for 70–80% of the heart'smass (Nag, 1980; Zak,1984; Popescu et al., 2006). In mammals, at birth or soon after, themajority of cardiac myocytes lose the ability to proliferate, thus heartgrowth occurs primarily via an increase in myocyte size (Soonpaa et al.,1996). The inability of adult cardiacmyocytes to divide has come undersome debate (Anversa & Nadal-Ginard, 2002; Anversa et al., 2002;Pasumarthi & Field, 2002). However, estimates of DNA labeling indicatethat DNA synthesis is taking place in a very small fraction of the totaladult cardiacmyocyte population (Nakagawa et al., 1988; Soonpaa et al.,1996; MacLellan & Schneider, 2000; Anversa et al., 2002; Pasumarthi &Field, 2002), indicating that the postnatal heart enlarges primarily by anincrease in myocyte size.

Myocytes are composed of bundles of myofibrils. Myofibrils containmyofilaments which consist of sarcomeres, the basic contractile unit ofthe heart. Myocytes are arranged in a circumferential and spiralorientation around the left ventricle, and need to contract simulta-neously to ensure the heart pumps with a normal rhythm. Intercalateddiscs, located at the bipolar ends of cardiacmyocytes, are responsible formaintaining cell–cell adhesion while allowing contractile force to betransmitted between adjacent cardiac myocytes (Estigoy et al., 2009).Growth of cardiac myocytes is dependent on the initiation of severalevents in response to an increase in functional load, including activationof signaling pathways, changes in gene expression, increases in the rateof protein synthesis, and the organization of contractile proteins intosarcomeric units (Fig. 1). Cardiac myocytes appear to have an intrinsicmechano-sensing mechanism. Stretch sensitive ion channels present intheplasmamembraneof cardiacmyocytes and structural proteins (suchas integrins) play a role in linking the extracellularmatrix, cytoskeleton,sarcomere, calcium handling proteins and nucleus (Knoll et al., 2003;Hoshijima, 2006). Thus, there is an interactive continuumfrom integrinsat the cell surface to the contractile apparatus and nucleus (Fig. 1).

1.3. Association between cardiac hypertrophy and heart failure

Understanding the molecular mechanisms responsible for theinduction of cardiac hypertrophy has been of great interest due to the

Fig. 2. Cardiac hypertrophy can be classified as physiological, which occurs during pregnanccardiac morphology and function. In contrast, hypertrophy that occurs in settings of disDevelopmental hypertrophy is associated with the normal growth of the heart after birth untshown in green, pathological heart growth is shown in red.

known association between cardiac hypertrophy and nearly all forms ofheart failure (Levy et al., 1990). Cardiac hypertrophy is also anindependent risk factor for myocardial infarction, arrhythmia andsudden death (Levy et al., 1990). In response to a chronic increase inload, there is an initial increase in heart mass to normalize wall stressand permit normal cardiovascular function at rest i.e. compensatedgrowth. However, if the chronic increase in wall stress is not relieved,the hypertrophied heart can dilate, contractile function falls and theheart can fail.

Heart failure affects approximately 1–3% of people in Westernsociety. The incidence of heart failure increases with age, affecting 3–4%of those over 45 years old, 5% of those aged between 60 and 69 years ofage, and 10% of people over the age of 70 (Davies et al., 2001; AIHW,2004; Thom et al., 2006; Lloyd-Jones et al., 2009). Symptoms of heartfailure patients include fatigue, insomnia, anxiety, depression, shortnessof breath, edema, dizziness, and nausea, all of which contribute to areduced quality of life for these patients (Blinderman et al., 2008).Withan aging population, rising rates of obesity and diabetes, as well as theavailability of interventions that prolong survival following cardiacinsults, the incidence of heart failure is likely to rise over the comingdecades. The costs associatedwith anexpandingnumberof patients andspecialized treatment strategies are expected to contribute significantlyto the economic burden caused by heart failure (Blinderman, et al.,2008). Currently there is no cure for heart failure, and long termsurvivalfollowing heart failure remains poor, with one third of patients dyingwithin a year of diagnosis (Zannad et al., 1999; Cowie et al., 2000;Bleumink et al., 2004; McMurray & Pfeffer, 2005). Thus, a number ofstudies have focused on identifying the molecular mechanismsassociated with cardiac hypertrophy and the transition to heart failure,to identify new therapeutic targets to prevent or reverse cardiachypertrophy and heart failure.

1.4. Cardiac hypertrophy and the athlete's heart

The athlete's heart has generally been defined as a benign increase inheartmass, associatedwithmorphological alterations, that represents a

y or in response to chronic exercise training, is reversible and characterized by normalease is detrimental for cardiac structure and function and can lead to heart failure.il adulthood. RV: right ventricle, LV: left ventricle. Normal/ physiological heart growth is


physiological adaptation to chronic training. Though, with attentionfrom media reports of sudden death in young athletes, it has beenquestioned whether highly trained athletes develop pathologicalconditions. Notably, there is currently no evidence in the healthypopulation (excluding persons with underlying cardiovascular diseaseor genetic disorders) showing that remodeling due to exercise trainingleads to long-termcardiac disease progression, cardiovascular disability,or sudden cardiac death (Maron & Pelliccia, 2006). The overall risk ofsudden death in athletes is not well defined but considered low. A 12-year survey in high-school athletes participating in organized sports in aUS state (Maron et al., 1998) reported a frequency of sudden death of1:200,000 per year (based on only 3 deaths among 1.4 million students;including27 sports). Suddendeath inyoung trained athletes in responseto physical exertion has largely been causally linked to congenital butclinically unsuspected cardiovascular disease (see Maron, 2003). Inlarge autopsy-based surveys of athletes in the US, hypertrophiccardiomyopathy is the most common cause of sudden death (account-ing for about one-third of events), followed by congenital coronary-artery anomalies. A wide range of other, largely congenital malforma-tions account for the remaining sudden deaths from cardiovasculardisease among athletes (Maron, 2003). Thus, it is generally acceptedthat cardiac hypertrophy in response to exercise is protective, in someinstances improves cardiac function, and does not progress to heartfailure. A comprehensive understanding of why cardiac hypertrophyprogresses to heart failure in a setting of disease, but does not inresponse to exercise, is considered important for identifying andtargeting the critical molecular mechanisms responsible for thetransition from hypertrophy to heart failure.

1.5. Distinct forms of cardiac growth and hypertrophy

1.5.1. Pathological and physiological cardiac growth and hypertrophyCardiac growth or hypertrophy can broadly be classified as either

physiological (“normal”) or pathological (“detrimental”). Physiolog-ical heart growth includes normal postnatal growth, pregnancy-induced growth, and exercise-induced cardiac hypertrophy. Incontrast, pathological growth occurs in response to chronic pressureor volume overload in a disease setting (e.g. hypertension, valvular

Fig. 3. Different stimuli induce different forms of cardiac hypertrophy. Pressure overload cauresults in concentric hypertrophy. Volume overload induces an increase in muscle mass via

heart disease), myocardial infarction or ischemia associated withcoronary artery disease, or abnormalities/conditions that lead tocardiomyopathy (e.g. inherited genetic mutations, diabetes) (Fig. 2).Both physiological and pathological heart growth are associated withan increase in heart size, however pathological hypertrophy is alsotypically associated with loss of myocytes and fibrotic replacement,cardiac dysfunction, and increased risk of heart failure and suddendeath (Levy et al., 1990; Weber et al., 1993; Cohn et al., 1997). Incontrast, physiological growth is associated with normal cardiacstructure, normal or improved cardiac function, and is reversible inthe instance of exercise- or pregnancy-induced hypertrophy (Ferrans,1984; Schaible & Scheuer, 1984; Fagard, 1997) (Fig. 2).

1.5.2. Concentric and eccentric hypertrophyPathological and physiological hypertrophy has classically been

subdivided as concentric or eccentric. These classifications are based onchanges in shape, which is dependent on the initiating stimulus(Grossman et al., 1975; Pluim et al., 2000) (Fig. 3). Concentrichypertrophy refers to an increase in relative wall thickness andcardiac mass, with a small reduction or no change in chamber volume.Concentric hypertrophy is characterized by a parallel pattern ofsarcomere addition leading to an increase in myocyte cell width(Fig. 3). Eccentric hypertrophy refers to an increase in cardiac masswith increased chamber volume, i.e. dilated chambers. Relative wallthickness may be normal, decreased, or increased. In eccentrichypertrophy, addition of sarcomeres in series leads to an increase inmyocyte cell length (Fig. 3) (Grossman et al., 1975).

A pathological stimulus causing pressure overload (e.g. hyperten-sion, aortic stenosis) produces an increase in systolic wall stresswhichresults in concentric hypertrophy (Grossman et al., 1975). In contrast,a stimulus causing volume overload (e.g. aortic regurgitation,arteriovenous fistulas) produces an increase in diastolic wall stressand results in eccentric hypertrophy (Grossman et al., 1975; Pluim etal., 2000). Clinical studies suggest that eccentric cardiac hypertrophyinduced by pathological stimuli poses a greater risk than concentriccardiac hypertrophy (Berenji et al., 2005).

Physiological stimuli can also produce concentric or eccentrichypertrophy. Aerobic exercise (also referred to as endurance training,

ses thickening of the left ventricle wall due to the addition of sarcomeres in parallel andthe addition of sarcomeres in series and results in eccentric hypertrophy.

Fig. 4. Four distinct features of cardiac hypertrophy include heart size, cardiac function, cardiac fibrosis and gene expression. The upper left quadrant shows representative images ofmouse hearts that have been subjected to a pathological (aortic banding; band) stimulus for one week, compared with sham (sham) operated controls, or mice subjected to aphysiological stimulus for four weeks (chronic swim training; exercise) compared with sedentary controls. An increase in heart size is observed in mice that have undergone aorticbanding (band) or chronic swim training (exercise) compared to sham and sedentary controls. The upper right quadrant depicts cardiac function as shown by M-modeechocardiography. Cardiac function is depressed in a mouse model of pathological (decompensated) hypertrophy but is conserved in a mouse model of physiological hypertrophy(exercise). The lower left quadrant depicts histological analysis of heart sections stained with Masson's trichrome; increased fibrosis is shown in blue and is only present inpathological hypertrophy. Representative sections from the left ventricular wall of untrained mice (control), aortic banded mice (pressure overload, band) and swim trained mice(exercise). Bar = 10 µm. Sections from sham operated mice were similar to those of untrained (control). The lower right quadrant shows gene expression changes associated withcardiac hypertrophy. Representative Northern blot showing total RNA from ventricles of sham, aortic banded (band), untrained (sedentary) and trained (exercise) mice. Expressionof GAPDH was determined to verify equal loading of RNA. There is increased expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), β-myosin heavy chain(β-MHC) and α-skeletal actin, and decreased expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA) and α-MHC in mice subjected to aortic banding (band) compared tocontrols, while gene expression remains relatively unchanged in exercised trained mice compared to sedentary controls.


isotonic or dynamic exercise e.g. long-distance running, swimming)and pregnancy increase venous return to the heart resulting involume overload and eccentric hypertrophy (Zak, 1984; Pluim et al.,2000; Eghbali et al., 2005). This type of eccentric hypertrophy isusually characterized by chamber enlargement and a proportionalchange in wall thickness, whereas eccentric hypertrophy in settings ofdisease is generally associated with thinning of the ventricular walls.Strength training (also referred to as isometric or static exercise, e.g.weight lifting, wrestling, throwing heavy objects) results in a pressure

Table 1Features of pathological and physiological hypertrophy.

Feature Pathological cardiac hype

Stimuli DiseasePressure or volume overloCardiomyopathy (familial

Cardiac morphology Increased myocyte volumFormation of new sarcomIncrease in heart size

Cardiac fibrosis YesApoptosis YesFetal gene expression Upregulation of ANP, BNPExpression of genes associated with contractile function Downregulation of SERCACardiac function DepressedMetabolism Decreased fatty acid oxid

Increased glucose utilizatReversible NoAssociation with heart failure and mortality Yes

load on the heart rather than volume load and concentric hypertrophy(Zak 1984; Pluim et al., 2000) (Fig. 3).

1.6. Distinct features of pathological and physiological hypertrophy

Despite comparable increases in heart size, pathological andphysiological hypertrophy are associated with distinct 1) structuraland functional, 2) metabolic, and 3) biochemical and molecularfeatures (Fig. 4, Table 1).

rtrophy Physiological cardiac hypertrophy

Aerobic exercise trainingad Postnatal growth, viral, diabetes, metabolic, alcoholic/toxic) Pregnancye Increased myocyte volumeeres Formation of new sarcomeres

Increase in heart sizeNoNo

, β-MHC, and α-skeletal actin Relatively unchanged2a, α-MHC Normal or increased

Normal or enhancedation Enhanced fatty acid oxidationion Enhanced glucose utilization

YesNo


1.6.1. Structural and functional featuresCardiac hypertrophy is associated with structural remodeling of

components of the ventricular walls to accommodate increases inmyocyte size, including changes in the fibrillar collagen networkand angiogenesis. Under basal conditions or a setting of physiolog-ical hypertrophy, the fibrillar collagen network provides structuralintegrity of adjoining myocytes, facilitating myocyte shorteningwhich translates into efficient cardiac pump function (Gunasinghe& Spinale, 2004). Pathological hypertrophy is associated with celldeath (apoptosis, necrosis) and the loss of myocytes is replacedwith excessive collagen (known as fibrosis). The main fibrillarcollagen present in cardiac fibrosis is type 1 collagen. Excessiveaccumulation of collagen stiffens the ventricles, which impairscontraction and relaxation, impairs the electrical coupling of cardiacmyocytes with extracellular matrix proteins, and reduces capillarydensity. Fibrosis and reduced capillary density increases oxygendiffusion distances, leading to myocardial ischemia, and is likely tocontribute to the transition from hypertrophy to failure (Guna-singhe & Spinale, 2004).

1.6.2. Cardiac metabolismIn the normal healthy heart, fatty acid oxidation is the main

metabolic pathway responsible for generating energy, accounting for60–70% of ATP production (van der Vusse et al., 1992); glucose andlactate metabolism account for approximately 30% of ATP synthesis.The heart is capable of switching energy substrates depending onworkload and the relative concentrations of fuel molecules in thebloodstream (see van der Vusse et al., 1992). This is considered anadaptive mechanism which allows the heart to produce a continuoussupply of ATP under various physiological conditions (e.g. fasting,during exercise, etc.).

Pathological cardiac hypertrophy is associated with decreases infatty acid oxidation and increases in glucose metabolism (Allard et al.,1994; Christe & Rodgers 1994; Davila-Roman et al., 2002). This switchin substrate utilization may be a protective mechanism, allowing theheart to produce more ATP per molecule of oxygen consumed (seevan Bilsen et al., 2009). This is reminiscent of what occurs during fetalcardiac development, when oxygen supply is limited and fatty acidtransport and metabolism are impaired (due to carnitine deficiencyand delayed maturation of enzymes involved in fatty acid oxidation).Thus, glucose is the primary substrate used by the fetal heart togenerate ATP (Ostadal, et al., 1999). In contrast, physiological cardiachypertrophy induced by exercise training is characterized byenhanced fatty acid and glucose oxidation (Gertz et al., 1988). Ofnote, in advanced pathological hypertrophy and failure, glucosemetabolism decreases as the heart becomes resistant to insulin,reducing the overall ability of the heart to generate sufficient ATP (seeNeubauer, 2007).

1.6.3. Biochemical and molecular featuresIn the 1970s and early 1980s it was recognized that physiological

hypertrophy (induced by exercise training/ thyroid hormone) wasassociated with elevations in myosin ATPase activity and enhance-ment of contractility, whereas pathological hypertrophy (induced byrenal hypertension, aortic banding) was associated with decreasedmyosin ATPase activity and depressed contractile function (Wikman-Coffelt et al., 1979; Rupp, 1981). Since then, there have been a numberof studies demonstrating that physiological and pathological cardiachypertrophy are associated with some distinct biochemical andmolecular signatures. Iemitsu et al. (2001) compared mRNA expres-sion in a rat model of pathological cardiac hypertrophy (spontane-ously hypertensive rat) and physiological hypertrophy (chronic swimtraining). The investigators reported a distinct pattern of geneexpression in the two models (Iemitsu et al., 2001). It is now wellrecognized that pathological cardiac hypertrophy is associated withdistinct alterations in cardiac contractile proteins (α- and β-myosin

heavy chain (MHC)), increased expression of fetal genes (e.g. atrialnatriuretic peptide (ANP), B-type natriuretic peptide (BNP), α-skeletal actin) but down-regulation of calcium-handling proteins(e.g. sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a)). Since thistime, generation of numerous transgenic and knockout mousemodelsin combination with models of physiological and pathologicalhypertrophy have allowed investigators to delineate signalingproteins that appear to play distinct roles in regulating physiologicaland pathological cardiac hypertrophy (discussed in detail inSection 3).

2. Experimental and genetic mousemodels utilized in the identification ofsignaling pathways that mediate cardiac hypertrophy

The definition of cardiac hypertrophy as either physiological orpathological has not been without contention (Dorn et al., 2003).However, there is now substantial evidence from animal studies thatthe different phenotypes associated with pathological and physiolog-ical hypertrophy can be due to distinct stimuli and activation of somedistinct signaling pathways, at least under certain conditions.

Studies utilizing genetic mouse models (transgenic and knockout)alone or in combination with morphologically distinct models ofhypertrophy (e.g. pathological, physiological, concentric and eccen-tric) have become powerful tools for understanding molecularpathways responsible for different forms of heart growth in vivo.Genetic mouse models have typically utilized the α-MHC promoter toachieve cardiac myocyte specific expression (Subramaniam et al.,1991), or the Cre-loxP system to generate cardiac-specific or inducibleknockout mice (Chien, 2001). Inducible transgenic mouse modelshave also been valuable as they allow investigators to switch on theactivity of the protein of interest in myocytes by injection of a drug(e.g. tamoxifen) at a specific time point, i.e. after completion ofdevelopmental growth (Fan et al., 2005b; Hoesl et al., 2008; Lu et al.,2009; Ruan et al., 2009). Commonly used experimental mousemodelsof pathological hypertrophy include pressure overload (constriction/banding of the renal, abdominal, ascending or transverse aorta),volume overload (aortocaval shunt), and minipump infusions ofvasoactive substances (e.g. isoproterenol, angiotensin II (Ang II)).Physiological models include treadmill running, freewheel runningand chronic swim training. Below, we have described hypertrophictriggers/stimuli, signaling proteins and cascades which appear to playan important role for the development of pathological or physiologicalhypertrophy.

2.1. Hypertrophic triggers/stimuli

In response to hemodynamic overload, cardiac myocytes aresubjected to mechanical stretch, and autocrine and paracrine humoralfactors including Ang II, endothelin 1 (ET-1), insulin-like growthfactor 1 (IGF1), transforming growth factor-β (TGF-β) and cardio-trophin 1 (CT-1) are released. These factors bind to receptors oncardiac cells, in turn activating intracellular signaling pathways thatleads to cell growth. Signaling cascades and proteins responsible forcardiac growth and hypertrophy are complex and extensive crosstalkhas been identified (Fig. 5). The subsequent sections of this reviewfocus on signaling cascades and proteins that have been reported toplay distinct roles in regulating pathological and physiologicalhypertrophy.

2.1.1. Physiological and pathological triggers/stimuliHuman and animal studies have demonstrated that certain factors

are preferentially released in response to pathological and physiolog-ical stimuli. It is well recognized that IGF1 is released during postnataldevelopment and in response to exercise training (Yeh et al., 1994;Conlon and Raff 1999; Koziris et al., 1999; Neri Serneri et al., 2001b;

Fig. 5. A schematic of the major signaling pathways involved in cardiac hypertrophy, showing cross-talk and integration of various pathways. N.B. due to the complex nature ofsignaling cascades and on-going discoveries it was not possible to illustrate all interactions.


Perrino et al., 2006), and IGF1 levels in the heart were increased inswim-trained rats (Scheinowitz et al., 2003). Furthermore, productionof cardiac IGF1 (but not Ang II or ET-1) was increased in professionalathletes comparedwith control subjects (Neri Serneri et al., 2001b). Incontrast, pressure overload is associated with elevated levels of Ang II,catecholamines and ET-1 (Schunkert et al., 1990; Arai et al., 1995;Yamazaki et al., 1999; Rapacciuolo et al., 2001; Yayama et al., 2004),and cardiac formation of Ang II was increased in heart failure patientswith hypertrophied hearts (Neri Serneri et al., 2001a).

3. Overview of signaling cascades/proteins implicatedin mediating physiological and pathological cardiac growth

The best characterized signaling cascades responsible for mediat-ing physiological and pathological cardiac hypertrophy are the IGF1-phosphoinositide 3-kinase [PI3K, (p110α)]-Akt pathway and Gαqsignaling (downstream of G protein-coupled receptors (GPCR)activated by Ang II, ET-1 and catecholamines), respectively (Fig. 6).Other signaling pathways associated with physiological cardiachypertrophy and/or protection include the gp130/JAK/STAT pathway,thyroid hormone signaling, and heat shock transcription factor 1(HSF1). In contrast, pathological hypertrophy has also been associatedwith abnormalities leading to enhanced PI3K(p110γ), mitogenactivated protein kinases (MAPKs), protein kinase C (PKC) and D(PKD), and calcineurin.

3.1. Signaling proteins/pathwaysimplicated in mediating physiological hypertrophy

3.1.1. IGF1-PI3K(p110α)-Akt pathwaySubstantial evidence from genetic mouse models has demonstrat-

ed the critical role of the IGF1-PI3K(p110α)-Akt pathway inregulating physiological cardiac growth.

3.1.1.1. Insulin-like growth factor (IGF1) receptor signaling. IGF1 is bestknown for being produced by the liver in response to growthhormone stimulation and is essential for normal fetal and postnatalgrowth and development (Adams et al., 2000). IGF1 is also producedby the heart (see reviews: Ren et al., 1999;McMullen, 2008) and bindsto a cell surface receptor, insulin-like growth factor 1 receptor(IGF1R), a receptor tyrosine kinase that activates downstreamsignaling proteins. A number of studies have examined the role ofIGF1 in the heart using gene targeted mice.

a) Mice with increased cardiac myocyte specific expression of IGF1(human IGF1B transgene expression driven by the α-MHCpromoter) had enlarged hearts with normal cardiac function(Reiss et al., 1996). A confounding factor of this study was thattransgene expression increased IGF1 secretion from cardiacmyocytes which resulted in a significant rise in systemic plasmalevels of IGF1 (approximately 80%) and an increase in other organweights. The increase in heart size was attributed to an increase in


cardiac myocyte number rather than myocyte size. This result wasunexpected given that the majority of mammalian cardiacmyocytes are thought to lose their ability to proliferate at birthor within the first few weeks of postnatal life (Soonpaa et al.,1996).

b) In a second study, IGF1 transgenic mice were generated using theα-skeletal actin promoter (transgene expression in heart andskeletal muscle) (Delaughter et al., 1999). Serum IGF1 levels werenot elevated but persistent transgenic expression was associatedwith increases in gut, liver, and spleen weight (Fiorotto et al.,2003). Up to 10 weeks of age, IGF1 transgenic mice displayedcardiac hypertrophy, which was associated with enhanced cardiacsystolic function i.e. physiological hypertrophy (Delaughter et al.,1999). However, the investigators concluded that the “physiolog-ical” cardiac phenotype ultimately progressed to pathologicalhypertrophy, because mice had depressed cardiac function by12 months of age (Delaughter et al., 1999).

c) We examined the role of IGF1 specifically in cardiac myocytes byover-expressing the IGF1R rather than IGF1 (transgenic expressionof human IGF1R using the α-MHC promoter) (McMullen et al.,2004b). Expression of the IGF1R was considered an advantagebecause it allowed examination of IGF1 signaling in the absence ofeffects of secreted IGF1 on other tissues or non-myocytes. At3 months of age, IGF1R transgenic mice had enlarged hearts(approximately 40% increase in weight, with a proportionalincrease of all chambers and ventricular wall thickness), increasedmyocyte size, no evidence of histopathology (e.g. necrosis, fibrosis,myocyte disarray) and enhanced systolic function (McMullen etal., 2004b). These characteristic features of physiological hyper-trophyweremaintained at 12–16 months of age (IGF1R transgenic

Fig. 6. A schematic overview of pathological and physiological hypertrophy outlining key diffFor simplicity we have focussed on the best characterized signaling pathways implicatehypertrophy. Other important mediators are described in detail in Section 3. Ang II: angiotenfactor 1, MAPK: mitogen-activated protein kinase, NE: norepinephrine, PI3K(p110α): phos

mice had enhanced systolic function in comparison to non-transgenic mice) (McMullen et al., 2004b). Thus, IGF1R transgenicmice did not progress to pathological hypertrophy with aging,which was observed in the earlier study (model b) (Delaughter etal., 1999). Consistent with the hypothesis that IGF1 activates PI3K(p110α) and Akt (a known downstream target of PI3K) to inducephysiological cardiac hypertrophy (Fig. 6), activation of PI3K andphosphorylation of Akt were elevated in hearts of IGF1R transgenicmice (McMullen et al., 2004b). In contrast, signaling proteinsdownstream of Gαq (implicated in pathological hypertrophy)including MAPKs and calcineurin were not activated in hearts ofIGF1R transgenic mice (McMullen et al., 2004b).

d) In corroboration with the idea that IGF1 signaling is critical forphysiological heart growth, cardiac myocyte-specific ablation ofthe IGF1R gene in mice attenuated the hypertrophic response toswim exercise training compared to non-transgenic mice (Kim etal., 2008b). A basal cardiac phenotype was not observed.

3.1.1.2. Phosphoinositide 3-kinase (PI3K, p110α) signaling. PI3Ks are afamily of enzymes and have been linked to a diverse group of cellularfunctions, particularly cell growth, survival, differentiation, andproliferation (Cantley, 2002). PI3K is a lipid kinase that releasesinositol lipid products from the plasma membrane which in turnmediate intracellular signaling (Toker & Cantley, 1997; Vanhaeseb-roeck et al., 1997). Activation of PI3Ks is coupled to both receptortyrosine kinases (e.g. insulin receptor and IGF1R) and GPCRs. Thereare three major classes of PI3Ks (classes I, II and III), which areclassified based on sequence homology in the catalytic domain,structure and substrate specificity (Vanhaesebroeck et al., 2001; Koket al., 2009). Class I PI3Ks are heterodimers and further divided into

erences in initiating stimuli, signaling pathways, cellular responses and cardiac function.d in mediating pathological (shaded red) and physiological (shaded green) cardiacsin II, ET-1: endothelin-1, GPCR: G protein-coupled receptor, IGF-1: insulin-like growthphoinositide 3-kinase p110α, RTK: receptor tyrosine kinase.


the subclasses IA and IB. Class IA PI3Ks consist of a p110 catalyticsubunit (α, β or δ) and a p85 or p55 regulatory subunit. The only ClassIβ PI3K is p110γ, which is regulated by p101 (Vanhaesebroeck et al.,1997). Of the Class I PI3Ks, p110α and p110γ are abundantlyexpressed in the heart. p110β is also expressed in the heart but at alower level (Crackower et al., 2002). The p110δ isoform of PI3K isexclusively expressed in leukocytes (Vanhaesebroeck & Waterfield,1999).

PI3Ks were first shown to regulate organ size in Drosophila. Over-expression of the Drosophila PI3K homolog, Dp110, resulted information of larger wings and eyes (Leevers et al., 1996). In contrast,expression of a catalytically inactive Dp110 caused the oppositephenotype, i.e. smaller wings and eyes (Leevers et al., 1996). Nullhomozygous mice for p110α were embryonically lethal due toproliferation defects in the embryo (Bi et al., 1999). Evidence thatPI3K activity regulates heart size was obtained from studies thatexpressed a cardiac-specific constitutively active (ca) form of PI3K(p110α) or dominant negative (dn) form of PI3K(p110α) intransgenic mice utilizing the α-MHC promoter (Shioi et al., 2000;McMullen et al., 2003). PI3K activity was increased by 6.5-fold inhearts of caPI3K transgenic mice, and hearts were 20% larger thannon-transgenic mice. The increase in heart size of the caPI3Kmice wasproportional, resembling physiological hypertrophy. In contrast, PI3Kactivity was 77% lower in hearts of dnPI3K transgenic mice, whichresulted in a 17% decrease in heart size compared to non-transgenicmice (Shioi et al., 2000). Changes in heart size were due to changes inmyocyte size rather than number (Shioi et al., 2000). Cardiac function,structure and life span were normal in caPI3K and dnPI3K transgenicmice under basal conditions (Shioi et al., 2000; McMullen et al., 2003).These studies demonstrated that PI3K(p110α) is critical for physio-logical postnatal growth of the heart.

It was later demonstrated that PI3K(p110α) is also critical forphysiological exercise-induced growth of the heart but not patholog-ical hypertrophy. Adult dnPI3K transgenic mice were subjected to aphysiological stimulus (exercise; chronic swim training) and apathological stimulus (pressure overload; ascending aortic banding).dnPI3K mice showed significant hypertrophy in response to pressureoverload, but an attenuated hypertrophic response to swim training,compared with non-transgenic mice (McMullen et al., 2003; McMul-len et al., 2007). These studies were also confirmed using a muscle-specific knockout approach of the p85α/p55α/p50α and p85β(global) regulatory subunits in mice (Luo et al., 2005), as well ascardiac-specific ablation of p110α (Lu et al., 2009). Thesemice showeda decrease in heart weight to body weight ratio of approximately 20%and 16%, respectively (Luo et al., 2005; Lu et al., 2009), similar to thatreported in dnPI3K mice (Shioi et al., 2000; McMullen et al., 2003).The small heart phenotype of p85α/p85β knockout mice wasaccompanied by a reduction in mean myocyte cell area, and miceexhibited an attenuated hypertrophic response to exercise training(Luo et al., 2005). Together, these studies support the critical role ofclass IA PI3Ks in the regulation of physiological cardiac hypertrophy.

Finally, to assess whether PI3K(p110α) was the critical mediatorresponsible for physiological growth in the IGF1R transgenic mice, wecrossed transgenic mice over-expressing IGF1R with dnPI3K trans-genic mice and examined heart size. Hearts of double transgenic mice(i.e. expressing both the IGF1R and dnPI3K transgenes) were notsignificantly different in size to that in dnPI3K mice alone (McMullenet al., 2004b). This result demonstrated that the physiological heartgrowth in the IGF1R transgenic mice was dependent on PI3K(p110α)signaling (McMullen et al., 2004b).

3.1.1.3. Akt. Akt, a serine/threonine kinase (also known as proteinkinase B), is a well characterized target of PI3K. The Akt family isinvolved in a number of cellular processes, including cell survival, cellcycle, metabolism, and protein synthesis. There are three isoforms ofAkt (Akt1, Akt2 and Akt3), each is encoded by distinct genetic loci, in

which the genes code for enzymes that are members of the serine/threonine-specific protein kinase family (Matsui & Rosenzweig,2005). The Akt homologue Dakt regulates cell and organ growth inDrosophila, in the same manner as PI3K; activation of Dakt increasedcell size whereas loss-of-function caused a reduction in cell size, buthad no impact on cell proliferation (Verdu et al., 1999; Rintelen et al.,2001). In mammals, Akt1 null mice had a 20% reduction in bodyweight (Cho et al., 2001). Although all three isoforms are broadlyexpressed, only Akt1 and Akt2 are highly expressed in the heart(Matsui & Rosenzweig 2005).

Initial characterization of the cardiac phenotypes of Akt transgenicmice led to confounding results. Phenotypes ranged from absence ofhypertrophy associated with protection from ischemia–reperfusioninjury to substantial hypertrophy associated with a pathologicalphenotype and premature death (Condorelli et al., 2002; Matsui et al.,2002; Shioi et al., 2002; Shiraishi et al., 2004; Shiojima et al., 2005). Thevarying phenotypes have been attributed to different degrees of Aktactivation, angiogenesis, and subcellular localization. Of note, Akt can beactivated by both receptor tyrosine kinases (e.g. IGF1R) and GPCR(Fig. 5), and appears to be differently regulated depending on theinitiating stimulus. Myostatin, an inhibitor of cardiac growth, reducedGPCR-induced Akt phosphorylation but not receptor tyrosine kinase(IGF1R)-induced phosphorylation in neonatal cardiac myocytes (Mor-issette et al., 2006). The biological significance of this differentialactivation is currently unclear.

More recent studies in Akt knockout mice suggest Akt1 is requiredfor physiological rather than pathological heart growth. Akt1knockout mice (normal cardiac phenotype under basal conditions)showed a blunted hypertrophic response to swim training but not topressure overload (DeBosch et al., 2006b). These findings arereminiscent of those in mice with reduced PI3K activity (McMullenet al., 2003; Luo et al., 2005). It is now generally accepted that Akt1mediates cardiac cell growth whereas Akt2 is important for cardiacmetabolism (DeBosch et al., 2006a,b).

Glycogen synthase kinase 3 (GSK3), a cellular substrate of Akt, isan important regulatory kinase with a number of cellular targets,including cytoskeletal proteins and transcription factors. Both GSK3isoforms (GSK3α and GSK3β) are expressed in the heart (Ferkey &Kimelman, 2000; Harwood, 2001; Hardt & Sadoshima, 2002). Initialreports demonstrated that GSK3β negatively regulated heart growthand that inhibition of GSK3β by hypertrophic stimuli was animportant mechanism for stimulating growth (Haq et al., 2000;Morisco et al., 2000; Morisco et al., 2001; Antos et al., 2002; Badorff etal., 2002). More recent studies have shown that GSK3α inhibitspostnatal cardiac growth and reduces pressure overload-inducedhypertrophy (Zhai et al., 2007). However, transgene expression wasassociated with increased fibrosis and apoptosis both under basalconditions and during pressure overload. Furthermore, the reducedhypertrophic phenotype in response to pressure overload wasassociated with severe cardiac dysfunction and heart failure (Zhai etal., 2007). Interestingly, the GSK3α and GSK3β isoforms appear tohave distinct roles in a setting of pressure overload. Phosphorylationof GSK3β was essential for the development of pathologicalhypertrophy whereas phosphorylation of GSK3α played a compen-satory role (Matsuda et al., 2008). Thus, selective modulation of thephosphorylation status of the two isoforms may be required tomaximize the therapeutic potential of modulating this kinase.

3.1.2. Gp130/JAK/STAT pathwayLeukemia inhibitory factor (LIF), CT-1, and other members of the

interleukin-6 cytokine family activate the gp130 receptor associatedwith the LIF receptor (Fig 5). Once activated, this cytokine receptorinteracts with janus kinase 1 (JAK1), leading to phosphorylation of thesignal transducer and activator of transcription (STAT) class oftranscription factors (Kodama et al., 1997; Pellegrini & Dusanter-Fourt 1997; Aoki & Izumo, 2001; Molkentin & Dorn 2001). Cardiac-


specific transgenic mice over-expressing STAT3 displayed cardiachypertrophy that was protective against doxorubicin-induced car-diomyopathy (Kunisada et al., 2000). In contrast, mice withventricular deletion of gp130 had normal cardiac structure andfunction under basal conditions, but displayed a rapid onset of dilatedcardiomyopathy in response to pressure overload (Hirota et al., 1999).However, expression of a dominant negative mutant of gp130 (todecrease activation of this pathway) appeared to protect transgenicmice against pressure overload-induced hypertrophy (Uozumi et al.,2001). Despite this discrepancy, the majority of data in the literaturesuggests that the gp130/JAK/STAT pathway has a protective role in theheart (see Fischer & Hilfiker-Kleiner, 2007; Boengler et al., 2008;Fischer & Hilfiker-Kleiner, 2008).

3.1.3. Thyroid hormone receptor signalingThyroid hormone is a classic hormonal mediator of normal

postnatal heart growth. The thyroid gland secretes two biologicallyactive hormones: thyroxine (T4, prohormone) and triiodothyronine(T3). T4 and T3 diffuse across the plasma membrane and T4 isconverted to T3 (Danzi & Klein 2002; Dillmann, 2002). Postnatal heartgrowth was reduced in a setting of depressed thyroid gland activity,whereas administration of excess thyroid hormone to animals led toan increase in heart weight (Bedotto et al., 1989; Hudlicka & Brown1996). Furthermore, administration of T4 in humans was associatedwith increased heart mass but no fall in systolic function (Ching et al.,1996), and patients with chronic hyperthyroidism have increasedcardiac contractility which is often associated with cardiac hypertro-phy (Forfar et al., 1982; Feldman et al., 1986). Thus, it has beensuggested that thyroid hormone induces physiological heart growth.

The biological effects of thyroid hormone have largely beenattributed to nuclear transcriptional mechanisms. T3 passes throughthe nuclear membrane to bind to nuclear thyroid hormone receptors(TRs), which act as transcription factors to directly repress or activatecardiac genes (Lazar & Chin 1990; Lazar 1993; Mangelsdorf et al.,1995; Danzi & Klein, 2002; Dillmann, 2002; Harvey &Williams, 2002).Thyroid hormone has been shown to regulate α- and β-MHC, cardiactroponin, SERCA2a, and voltage gated potassium channels (Izumo etal., 1986; Rohrer & Dillmann, 1988; Nishiyama et al., 1998; Danzi &Klein, 2002). Inmammals TRs are encoded by two genes: TRα and TRβ(Lazar, 1993; Harvey & Williams, 2002). Thyroid hormone treatmentincreased heart mass by approximately 64% in wildtype mice, 44% inTRα knockout mice but only 6% in TRβ knockout mice, suggesting thatTRβ plays a predominant role in regulating heart growth (Weiss et al.,2002).

More recently, cytosolic and membrane-initiated effects of thyroidhormones have been reported (Bassett et al., 2003; Farach-Carson &Davis, 2003). Kenessey andOjamaa demonstrated a direct interaction ofcytosol-localized TRα1 with the p85α regulatory subunit of PI3K inneonatal rat ventricular myocytes (Kenessey & Ojamaa, 2006). Thisinteraction was shown to be critical for T3-induced protein synthesis.The authors concluded that rapid T3 mediated activation of PI3K byTRα1 may underlie the mechanisms via which thyroid hormoneinduces physiological heart growth (Kenessey & Ojamaa, 2006) (Fig 5).

3.1.4. Heat shock transcription factor 1Sakamoto and colleagues identified HSF1 as a promising critical

mediator of physiological cardiac hypertrophy from a genetic profilingstudy that compared gene expression in hearts from rats subjected topressure overload with exercise trained rats (voluntary runningwheel). Gene expression of HSF1, which regulates heat shock proteins(Hsp) including Hsp70 and Hsp27, was upregulated in hearts fromexercise trained rats but not in hearts subjected to pressure overload(Sakamoto et al., 2006). To examine whether HSF1 had a protectiverole in exercise-induced cardiac hypertrophy, HSF1-deficient hetero-zygote mice (HSF1+/−) were subjected to voluntary wheel runningfor 4 weeks. Interestingly, exercise-induced hypertrophy was not

blunted in HSF1+/− but cardiac function was significantly reduced(Sakamoto et al., 2006).

3.2. Signaling proteins/pathwaysimplicated in mediating pathological hypertrophy

3.2.1. G proteinsG proteins can be divided into twomain subgroups: heterotrimeric

G proteins and small-molecular-weight monomeric G proteins (smallG proteins).

3.2.1.1. Heterotrimeric G proteins. Heterotrimeric G proteins consist ofthree subunits (α, β and γ) and couple to GPCR. Binding of an agonistto the GPCR leads to dissociation of the Gα and Gβγ subunits,followed by activation of downstream signaling pathways (Gutkind,1998a,b; Rockman et al., 2002). Isoforms of the heterotrimeric Gproteins are largely determined by the isoform of the α subunits,which fall into four subfamilies: Gs, Gi, G12, and Gq (e.g. Gαq, Gα11)(Simon et al., 1991; Neer, 1995).

In response to a pathological stimulus (e.g. pressure overload),hormones/vasoactive factors such as Ang II, ET-1 and noradrenaline(norepinephrine, NE) are released and induce cardiac growth(Schunkert et al., 1990; Arai et al., 1995; Yamazaki et al., 1999;Rapacciuolo et al., 2001; Yayama et al., 2004). These ligands bind toGPCR: Ang II receptor type 1 (AT1 receptor), endothelin receptors (ETAand ETB) and α1-adrenergic receptors (ARs), respectively. This causesactivation of Gαq/11 and downstream signaling proteins, includingphospholipase C (PLC), MAPKs, PKC and protein kinase A (PKA).Transgenic mouse studies have highlighted the critical role of Gαq/11

in mediating pathological cardiac hypertrophy (Fig. 6). Cardiac-specific transgenic mice over-expressing Gαq developed cardiachypertrophy that was associated with cardiac dysfunction andpremature death (D'Angelo et al., 1997; Mende et al., 1998). Incontrast, mice lacking G proteins (Gαq/11) in cardiac myocytes andcardiac-specific transgenic mice expressing a peptide specific forinhibiting Gq-coupled receptor signaling displayed no hypertrophy ora significantly blunted response to pressure overload (Akhter et al.,1998; Wettschureck et al., 2001). Taken together, these studiessuggest that the Gαq/11 pathway is important for the induction ofpathological hypertrophy.

3.2.1.1.1. Angiotensin II receptors. Ang II is the principal vasoactivesubstance of the renin–angiotensin system with a variety ofpathophysiological actions in the cardiovascular system via systemicand local effects including vasoconstriction, aldosterone release, andcell growth (Zimmerman & Dunham, 1997; de Gasparo et al., 2000).Two pharmacologically distinct Ang II receptors have been cloned(AT1 and AT2). Rodents have two AT1 receptor isoforms (AT1A andAT1B) (de Gasparo et al., 1995; Lorell 1999). The heart contains a localrenin–angiotensin system which is activated in response to hemody-namic stress (e.g. pressure overload) (Yamazaki & Yazaki, 1997;Lijnen & Petrov, 1999). It is well established that blocking Ang IIformation with angiotensin converting enzyme inhibitors (ACEI)attenuates pressure overload-induced hypertrophy in animal modelsand humans (Sadoshima et al., 1996; Zhu et al., 1997; Lijnen andPetrov 1999; Yamazaki et al., 1999; Devereux 2000; Modesti et al.,2000).

Hypertrophy due to activation of the AT1 receptor in rodent cardiacneonatal myocytes or mouse models has been associated withactivation of MAPKs, increased intracellular calcium, PKC, andtransactivation of the epidermal growth factor receptor (EGFR)(Sadoshima & Izumo, 1993; Miyata & Haneda, 1994; Sadoshima etal., 1995; Kagiyama et al., 2002; Thomas et al., 2002; Chan et al., 2006).Under basal conditions, single global Ang II receptor knockout mice(AT1A, AT1B, AT2) have been reported to have no cardiac phenotype ora small decrease in heart mass (Hein et al., 1995; Ichiki et al., 1995;Hamawaki et al., 1998; Harada et al., 1998; Oliverio et al., 1998;


Gembardt et al., 2008). Interestingly, double knockouts lacking AT1Aand AT1B had smaller hearts than AT1A alone, whereas the reductionwas less pronounced in triple knockout mice lacking AT1A, AT1B andAT2 (Gembardt et al., 2008). Cardiac-specific AT1 transgenic micedeveloped pathological hypertrophy and died prematurely of heartfailure (Paradis et al., 2000). Unexpectedly, pressure overload-induced hypertrophy was not blunted in AT1A knockout mice(Hamawaki et al., 1998; Harada et al., 1998), possibly suggestingthat AT1B is able to compensate for loss of AT1A. Mice with a gain offunction mutated AT1A receptor did not display cardiac hypertrophybut developed progressive cardiac fibrosis and diastolic functionabnormalities (Billet et al., 2007). Though, this study is confounded bya modest increase in blood pressure in the mutant mice. Cardiac-specific AT2 transgenic mice had no cardiac phenotype (Masaki et al.,1998), but pressure overload-induced hypertrophy was inhibited inAT2 knockout mice (Senbonmatsu et al., 2000). While it is reasonablyclear that Ang II is critical for mediating cardiac hypertrophy, theprecise role of Ang II receptor subtypes requires further examination(see Billet et al., 2008)). In addition, recent studies have demonstratedthe cardiovascular effects of a number of breakdown products of AngII including Ang 1–7, Ang III and Ang IV; as well as new mechanismsconcerning the functional regulation of Ang II receptors such asreceptor dimerization, ligand-independent activation, receptor-inter-acting proteins, and the existence of an agonistic antibody against theAT1 receptor (Jones et al., 2008; Mogi et al., 2009). The role of thesepeptides and new regulation of Ang II receptors in relation to cardiachypertrophy also requires further investigation.

3.2.1.1.2. Endothelin-1 receptors. ET-1 is the predominant endothe-lin in the heart and is a potent hypertrophic stimulus in neonatalcardiacmyocytes (Shubeita et al., 1990). ET-1 binds to two GPCRs: ETAand ETB. ETA receptors account for 90% of endothelin receptors oncardiac myocytes (Kedzierski & Yanagisawa, 2001). Ang II increasedET-1 levels in rat cultured cardiac myocytes, and an ETA antagonist(BQ123) reduced Ang II-induced myocyte hypertrophy (Ito et al.,1993). ETA receptor antagonists (alone or in combination with ETBreceptor antagonists) have been shown to attenuate pathologicalhypertrophic responses in animal models (see Brunner et al., 2006).Though, cardiac myocyte specific ETA knockout mice displayed anormal hypertrophic response to Ang II (Kedzierski et al., 2003).

A number of clinical trials have assessed the potential of ET-1antagonists to treat heart failure patients; results have largely beendisappointing, and/or remain unpublished (reviewed by (Seed et al.,2001; Rich & McLaughlin, 2003; Kelland & Webb, 2006; Kirkby et al.,2008)). In the majority of clinical trials using ET-1 antagonists [eithernon-selective for ETA or ETB (e.g. bosentan, tezosentan) or selective forETA (e.g. darusentan)] heart failure patients developed adverse sideeffects without improvement in cardiac remodeling or clinicalsymptoms (Louis et al., 2001; Kalra et al., 2002; Luscher et al., 2002;Rich & McLaughlin, 2003; Anand et al., 2004; Packer et al., 2005;Kaluski et al., 2008).

3.2.1.1.3. Adrenergic receptors (ARs). Catecholamines activate ARs(members of the GPCR superfamily) (Scheuer 1999; Lomasney &Allen, 2001; Rockman et al., 2002). There are three major ARsubfamilies: α1-AR, α2-AR, and β-AR. At least 6 types of ARs arepresent in the mammalian heart (three α1-ARs: α1A, α1B, α1D andthree β-ARs: β1, β2, β3), with β1-ARs predominating, accounting forapproximately 80% of the β-ARs in the healthy heart (Xiang & Kobilka,2003; Barki-Harrington et al., 2004; Salazar et al., 2007; Woodcock etal., 2008). ARs are coupled to Gαq, Gαs, and Gαi, leading tomodulation of adenylate cyclase, PLC and ion channels (Rockman etal., 2002). Specifically, α1A, α1B, and α1D-ARs activate Gαq signaling,β1-ARs couple to Gαs, and β2-ARs couple to Gαs and Gαi (Exton, 1985;Garcia-Sainz et al., 1999; Rockman et al., 2002). Species-dependentdifferences exist between the functions of β1- and β2-AR subtypes inthe heart which may be attributed to differential coupling to Gαs andGαi (see Kaumann et al., 1999). In the human heart, β2-ARs appear to

largely couple to the Gαs/cAMP pathway (Kaumann et al., 1999). Therole of β3-ARs in the heart remains unclear (see Barki-Harrington etal., 2004; Kaumann & Molenaar, 2008).

Heart failure patients have elevated circulating catecholaminesand increased adrenergic drive, which initially increases contractilityand may be beneficial. However, prolonged adrenergic drive isdetrimental and associated with desensitization and downregulationof β-ARs (Bristow, 2000). This is consistent with findings fromcardiac-specific transgenic mice over-expressing β1-ARs. Before15 weeks of age, transgenic mice displayed increased cardiaccontractility compared to controls. However, cardiac function pro-gressively fell in β1-AR transgenic mice after 16 weeks and the micerapidly developed cardiac dysfunction and heart failure (Engelhardtet al., 1999). Progressive deterioration in cardiac function withchronic transgenic expression of β1-AR was later confirmed byanother report (Bisognano et al., 2000).

Cardiac-specific transgenic mice expressing a dominant negativeβ-AR receptor kinase 1 (β-ARK1/GRK2; dominant negative mutantrestoresβ-AR signaling;β-ARK1phosphorylatesβ-ARs leading to theirdesensitization) were protected against pathological hypertrophy andheart failure (Koch et al., 1995), and targeted deletion of GRK2 incardiac myocytes of mice prevented and rescued heart failure inducedbymyocardial infarction (Raake et al., 2008). In this respect, it has beendifficult to explain why β-AR agonists are poorly tolerated in heartfailure patients but β-blockers have a protective role (Bristow, 2003;Molenaar & Parsonage, 2005, discussed in further detail in Section 8.1).Though it has been suggested that at the molecular level, inhibition ofβ-ARK1/GRK2 shares a number of properties with β-blockade asopposed to β-AR agonism (Rockman et al., 2002). For instance, β-ARagonists promote desensitization and receptor downregulation due toconstant activation of the β-AR system. In contrast, inhibition of β-ARK1 may allow β-ARs to return to a more normal state of signalingbecause desensitization will be inhibited (Rockman et al., 2002).

While it is generally accepted that chronic stimulation of the β-ARsystem has an adverse effect on the heart that contributes to thepathogenesis of heart failure, preservation of normal β-AR-G proteincoupling is critical during times of need, such as periods of stress andduring exercise (Christensen & Galbo, 1983; Lefkowitz et al., 2000;Rockman et al., 2002). In this instance, acute versus chronic activationof β-ARs may explain differences in phenotype observed withpathological and physiological hypertrophy. Plasma resting levels ofcatecholamines were significantly higher in a mouse model ofpathological hypertrophy induced by chronic pressure overload incomparison to a mouse model of physiological hypertrophy inducedby swim training (Perrino et al., 2006).

The role of AR subtypes inmediating cardiac hypertrophy based ongenetically modified mouse models has been described in detail (seeDu, 2008). Global knockout mice deficient of β1 and β2-ARs displayedan attenuated hypertrophic response to pressure overload, withreduced fibrosis (Kiriazis et al., 2008). Based on various transgenic andknockout models, α1B-AR and β2-AR appear to contribute tomaladaptation and the onset of heart failure in a setting of pressureoverload, whereas activation of α1A-AR may be beneficial (Du, 2008).Of note, in rat neonatal cardiac myocytes, it was shown that β2-ARsthat couple with Gi proteins mediate cardiac protection due toactivation of the PI3K-Akt pathway (Chesley et al., 2000). Further-more, α1-ARs were critical for normal postnatal heart growth in malebut not female mice (O'Connell et al., 2003), and protected the heartagainst pressure overload-induced maladaptive hypertrophy (O'Con-nell et al., 2006).

3.2.1.2. Small G proteins (also called GTPases). The family of small Gproteins can be divided into 5 subfamilies (Ras, Rho, ADP ribosylationfactors, Rab, and Ran). Small G proteins act as molecular switches,which link receptors to downstream signaling cascades. Ras and Rhocan be activated in myocytes in response to Ang II, ET-1,

Fig. 7. ERK1/2 appears to contribute to hypertrophic responses via two distinctmechanisms. Stimulation of GPCRs leads to dissociation of Gq proteins. A) The Gαsubunit of Gq activates traditional MAP kinase signaling cascades, resulting inphosphorylation and activation of ERK1/2 by MEK1/2. This in turn leads to proteinsynthesis and cell growth. B) Association of Gβγ subunits with the Raf1/MEK/ERK1/2complex is necessary for autophosphorylation of ERK1/2 at residue Thr188 andlocalization of ERK1/2 in the nucleus. This leads to phosphorylation of nuclear targets(such as Elk1, MSK1 and c-Myc) and transcription of hypertrophic genes.


phenylephrine (PE) and mechanical stress and have been implicatedin the development of cardiac hypertrophy (Ramirez et al., 1997a;Aoki et al., 1998; Aikawa et al., 1999; Chiloeches et al., 1999; Clerk andSugden, 2000; Clerk et al., 2001). Cardiac-specific transgenic miceexpressing a constitutively active form of Ras or over-expressingRab1a developed pathological cardiac hypertrophy (Hunter et al.,1995; Wu et al., 2001). Furthermore, using a Rho-kinase inhibitor(Fasudil), it was shown that Rho-kinase was critical for pressureoverload-induced pathological hypertrophy in rats but not swim-ming-induced physiological cardiac hypertrophy (Balakumar & Singh,2006).

3.2.2. PI3K(p110γ) signalingIn contrast to the p110α isoform of PI3K (coupled to RTKs e.g.

IGF1R), PI3K(p110γ) is coupled to GPCRs (specific GPCR not alldefinitively defined but thought to include Gαs/Gαi/Gαq e.g. adren-ergic receptors, Ang II receptors and endothelin receptors) andappears to have a detrimental effect in the heart (Oudit et al., 2004).PI3K(p110γ) does not affect heart size under basal conditions but is anegative regulator of cardiac contractility, as PI3K(p110γ) knockoutmice displayed enhanced contractile function (Crackower et al.,2002). PI3K(p110γ) may have an impact on heart growth in settingsof pathological stress (Naga Prasad et al., 2000; Oudit et al., 2003),although the role of PI3K(p110γ) in the diseased heart is complex andappears to differ depending on the nature of the pathologicalstimulus. PI3K(p110γ) knockout mice were protected from heartfailure induced by chronic activation of β-ARs, displaying lesshypertrophy and fibrosis, and better cardiac function than controls(Oudit et al., 2003). However, PI3K(p110γ) knockout mice displayedan accelerated progression to dilated cardiomyopathy in response topressure overload (Patrucco et al., 2004; Oudit & Kassiri, 2007). PI3K(p110γ) might contribute to cardiac dysfunction via its effects on β-AR internalization and regulation of phosphodiesterases (Fig. 5)(Oudit & Kassiri, 2007; Pretorius et al., 2009b). Downregulation anddesensitization of β-ARs is detrimental for heart function (Bristow etal., 1982; Perrino et al., 2007), and is dependent on the binding ofp110γ to β-ARK1 (Naga Prasad et al., 2001). Expression of acatalytically inactive p110γ mutant or disruption of the interactionbetween β-ARK1 and p110γ restored β-AR signaling and contractilefunction in transgenic mice subjected to chronic β-AR stimulation(Nienaber et al., 2003; Perrino et al., 2005; Perrino et al., 2007). PI3K(p110γ) may also reduce cardiomyocyte contractility by regulatingthe activity of phosphodiesterases (PDEs) (Patrucco et al., 2004;Kerfant et al., 2007). PDEs hydrolyse cAMP, a secondmessenger whichplays a critical role in mediating Ca2+ release from the sarcoplasmicreticulum to induce contraction. PDE inhibitors improve contractilefunction by increasing intracellular cAMP levels, however the safety ofPDE inhibitors as therapeutic agents in patients with heart failure isstill being investigated (see Osadchii, 2007 for review).

3.2.3. Mitogen activated protein kinase (MAPK) pathwaysMAPKs are divided into 3 subfamilies based on the terminal kinase

in the pathway: the extracellular signal-regulated kinases (ERKs), thec-Jun amino-terminal kinase (JNKs), and the p38-MAPKs (Clerk &Sugden, 1999; Widmann et al., 1999; Pearson et al., 2001). All threetypes of MAPKs are activated in cultured cardiacmyocytes in responseto GPCR agonists (couple to Gαq: AT1 receptors, endothelin receptorsand α1-ARs) and mechanical stress, as well as in pressure overloadedhearts and failing human hearts, but the exact role of MAPKs hasremained unclear (Yamazaki et al., 1993; Sadoshima et al., 1995;Komuro et al., 1996; Sugden & Clerk, 1998; Cook et al., 1999; Espositoet al., 2001; Pearson et al., 2001; Takeishi et al., 2001; Purcell et al.,2007).

3.2.3.1. ERK1/2. ERKs are protein kinases that phosphorylate a range ofcytosolic and nuclear substrates (see Chen et al., 2001b for review).

ERK1/2 are ubiquitously expressed (Boulton et al., 1991) andactivation has been reported in numerous settings of cardiachypertrophy and failure (see Muslin, 2008) however it is still unclearwhether ERK1/2 is a critical mediator of hypertrophic responses.ERK1/2 was activated in response to agonists that induce pathologicalheart growth, such as Ang II, ET-1 and NE, but not in response to thephysiological hypertrophic agonist IGF1 (Clerk et al., 2006). In isolatedcardiac myocytes, activation of ERK1/2 was essential for proteinsynthesis (a requirement for cell growth) following stimulation withhypertrophic agonists that signal via Gq protein coupled receptors(Wang & Proud, 2002). Consistent with this finding, expression of adominant negative mutant of Raf-1 (a MAPK kinase kinase down-stream of Gαq; Fig. 5) blunted cardiac hypertrophy in mice subjectedto pressure overload, implicating ERK1/2 in the development ofpathological cardiac hypertrophy (Harris et al., 2004). However,transgenic mice expressing cardiac-specific constitutively activeMAPK kinase 1 (MEK1; a MAPK kinase immediately upstream ofERK1/2; does not activate JNK or p38-MAPK) developed a physiolog-ical rather than a pathological phenotype, which was characterized byconcentric cardiac hypertrophy, enhanced systolic cardiac functionand no interstitial fibrosis (Bueno et al., 2000). Furthermore, loss ofERK1 (global knockout mice) had no effect on heart size in micesubjected to pressure overload or swim training, indicating that ERK1is not a critical mediator of pathological or physiological hypertrophy,or that the remaining ERK2 activity was sufficient to drive thehypertrophic response (Purcell et al., 2007). Reduced expression ofERK2 (ERK2+/− mice; ERK2−/− mice are embryonically lethal) aloneor in mice deficient for ERK1 (ERK1−/−ERK2+/− mice) also failed toblock hypertrophy induced by pressure overload or swim training(Purcell et al., 2007). Together, these studies suggest that activation ofERK1/2 is sufficient, but not critical, for inducing cardiac hypertrophy,although the results of the latter study were confounded by the factthat the ERK1−/− and ERK2+/− mice were not cardiac-specific.


Induction of ERK1/2 kinase activity requires phosphorylation ofthe threonine and tyrosine residues within the TEY motif of theactivation loop by MEK1/2 (Anderson et al., 1990; Payne et al., 1991;Robbins et al., 1993). A recent study reported that autophosphoryla-tion of ERK2 at residue Thr188 promoted nuclear localization andsubsequent phosphorylation of hypertrophic factors, including Elk1,MSK1 and c-Myc (Lorenz et al., 2009). This occurred followingassociation of the Raf/MEK/ERK complex with the βγ subunits of Gq

proteins (Lorenz et al., 2009). Thr188 phosphorylation appears to be akey event in the development of ERK1/2-mediated cardiac hypertro-phy, as transgenic mice with suppressed ERK2 Thr188 phosphoryla-tion were resistant to cardiac hypertrophy induced by pressureoverload, while mice with enhanced ERK2 Thr188 phosphorylationdisplayed more pronounced hypertrophy compared to wildtype mice(Lorenz et al., 2009). Phosphorylation of Thr188 was also evident inbiopsies from human failing hearts, suggesting that ERK2 autopho-sphorylation of Thr188 is clinically relevant (Lorenz et al., 2009). Thus,ERK1/2 appears to contribute to cardiac hypertrophic responses viatwo distinct mechanisms (Fig. 7). Activation of the traditional MAPKsignaling cascade (Raf/MEK/ERK) following binding of Gαq proteins toGPCRs results in phosphorylation of ERK1/2 within the TEY motif andinduction of ERK1/2 kinase activity. Subsequent phosphorylation ofsubstrates (such as p90 ribosomal S6 kinase (Lorenz et al., 2009))maycontribute to cell hypertrophy by increasing protein synthesis. Thismechanism may be responsible for driving the physiological hyper-trophy observed in theMEK1 transgenicmice. Secondly, interaction ofthe Raf/MEK/ERK complex with Gβγ proteins causes autophosphor-ylation of ERK2 at Thr188. This results in nuclear localization, allowingERK1/2 to phosphorylate nuclear targets, which in turn promotestranscription of hypertrophic genes. This event may be critical forinducing the maladaptive phenotype associated with pathologicalhypertrophic responses (Fig 7.)

3.2.3.2. ERK5. ERK5 (also known as big MAP kinase 1, BMK1) may playa role in mediating pathological eccentric cardiac hypertrophy, astransgenic mice expressing constitutively active MEK5 developedeccentric cardiac hypertrophy which progressed to dilated cardiomy-opathy and death (Nicol et al., 2001).

Table 2JNK mouse models and their phenotype under basal conditions and in response to pressure o

Mouse model Basal phenotype

Versus Ntg/WT

caMEK7(cardiac-specific)

↔

dnMEK4(cardiac-specific by adenovirus-mediated gene transfer)

n/a

dnJNK1/2(cardiac-specific)

↑

Jnk1+/−/Jnk2−/−

(targeted deletion, global)↑

MEK4−/−

(cardiac-specific)↔

MEKK1−/−

(targeted deletion, global)↔

Jnk1−/−


Jnk2−/−


Jnk3−/−


Key:↔ = JNK has no effect on heart growth, possibly due to redundancy of isoforms.↑ = Indicates JNK antagonizes pathological growth.↓ = JNK is essential for pathological growth.n/a = not examined/assessed.

3.2.3.3. JNKs. The JNK family consists of at least ten isoforms, derivedfrom three genes: JNK1, JNK2 and JNK3 (Waetzig & Herdegen, 2005).JNK1 and JNK2 are ubiquitously expressed, whereas JNK3 has a morerestricted expression profile in the heart, brain and testis (Waetzig &Herdegen, 2005). JNK was activated in hearts from heart failurepatients (Cook et al., 1999) and in the remote myocardium ofinfarcted rat hearts (Li et al., 1998). A number of in vitro studies havesuggested that JNKs may be important regulators of pathologicalhypertrophy (Bogoyevitch et al., 1996; Ramirez et al., 1997a;Choukroun et al., 1998; Wang et al., 1998b; Choukroun et al., 1999),although in vivo studies have been more difficult to interpret(described below and summarized in Table 2).

JNK is phosphorylated and activated by MAPK kinase 4 (MEK4) andMEK7 (Fig. 5), and preferentially upregulated by MAPK kinase kinase 1(MEKK1) (Fig 5). Transgenicmicewith cardiac-specific activation of JNK(via constitutive activation of MEK7) did not develop cardiac hypertro-phy but died prematurely from congestive heart failure (Petrich et al.,2003). Several loss of function approaches have also been utilized todetermine the role of JNKs in pathological cardiac hypertrophy. Pressureoverload-induced hypertrophy was attenuated in dnMEK4 transgenicmice (Choukrounet al., 1999), andMEKK1wasessential for pathologicalcardiac hypertrophy and dysfunction induced by cardiac-specifictransgenic expression of Gαq (Minamino et al., 2002). These datasuggest JNKs may be necessary regulators of pathological cardiachypertrophy. However, dnJNK1/2 transgenic mice and JNK1/2 gene-targetedmicedisplayed anenhancedhypertrophic response topressureoverload (Liang et al., 2003), suggesting JNKs antagonize cardiacgrowth. Furthermore, cardiac-specific MEK4 knockout mice withreduced JNK activity displayed normal cardiac growth and functionunder basal conditions (Liu et al., 2009). However, following aortic-banding and chronic β-adrenergic stimulation, unlike the dnMEK4transgenic mice, cardiac specific MEK4 knockout mice had enhancedcardiac growth, increased hypertrophic gene transcription and ventric-ular fibrosis compared to wildtype aortic-banded controls. Followingswim training, the hypertrophic response was unchanged compared towildtype controls in thismodel (Liu et al., 2009). NullMEKK1 transgenicmice had comparable heart weights to wildtype mice under basalconditions. In response to aortic-banding,MEKK1−/−mice displayed anenhanced hypertrophic response rather than a blunted response after

verload as assessed by heart weight/body weight or left ventricular/body weight ratios.

Pressure overload Reference

Hypertrophic response versus Ntg/WT

n/a Petrich et al., 2004

↓ Choukroun et al., 1999

↑ Liang et al., 2003

↑ Liang et al., 2003

↑ Liu et al., 2009

↑ Sadoshima et al., 2002

↔ Tachibana et al., 2006



Table 3p38 mouse models and their phenotype under basal conditions and in response to pressure overload as assessed by heart weight/body weight or left ventricular/body weight ratios.

Mouse model Basal phenotype Pressure overload Reference

Versus Ntg/WT Hypertrophic response versus Ntg/WT

dn-p38α(cardiac-specific, Black Swiss background)

↔ ↔ Zhang et al., 2003a

dn-p38α(cardiac-specific, FVB/N background)

↑ ↑ Braz et al., 2003

dn-p38α(cardiac-specific females compared to males)

↔ ↑ Liu et al., 2006

p38α CKO(cardiac-specific KO)

↔ ↔ Nishida et al., 2004

dn-p38β(cardiac-specific)

↔ ↔ Zhang et al., 2003a

dnMEK3(cardiac-specific)

↑ ↑ Braz et al., 2003

dnMEK6(cardiac-specific)

↑ ↑ Braz et al., 2003

MEK3(cardiac-specific)

↔ n/a Liao et al., 2001

MEK6(cardiac-specific)

↔ n/a Liao et al., 2001

Key:↔ = p38 has no effect on heart growth.↑ = p38 is essential for pathological hypertrophy.n/a = not examined/assessed.


14 days compared to wildtype controls (Sadoshima et al., 2002).Furthermore, aortic-banded MEKK1−/− mice had a higher mortalityrate and congestive heart failure compared to wildtype banded mice.This study implies that cardiac hypertrophy induced by pressureoverload occurs in the absence of JNK activation. In further support ofthe latter, mice with selective deletion of the three JNK genes (Jnk1−/−,Jnk2−/− and Jnk3−/−) subjected to aortic-banding developed cardiachypertrophy that was comparable to wildtype mice (Tachibana et al.,2006). Thus, it appears individual members of the JNK family are notrequired to induce cardiac growth, or that the JNK isoforms arefunctionally redundant.

3.2.3.4. p38-MAPK. p38-MAPK is an important mediator of numerousbiological functions including cell growth, cell proliferation, cell cycleand cell death, and is considered a critical component of stressresponse pathways (Wilson et al., 1996; Bassi et al., 2008). In theheart, p38-MAPK is known to be activated during ischemia, and p38-MAPK activity was increased in the myocardium from patients withischemic heart disease (Cook et al., 1999). p38-MAPK has beenimplicated in the regulation of cardiac gene expression, cardiacmyocyte apoptosis, myocyte hypertrophy, contractility, remodelingand metabolism (Liao et al., 2001; Petrich & Wang, 2004; Baines &Molkentin, 2005; Wang, 2007).

The p38-MAPK family consists of four isoforms (α, β, δ and γ),though it appears only α and β are expressed in the heart (Jiang et al.,1997; Clark et al., 2007). The p38α isoform is predominatelyexpressed in the human and rodent myocardium (Lemke et al.,2001; Braz et al., 2003). The role of p38α and p38β in the heart hasbeen examined extensively using both transgenic and knockoutmouse models. As with JNK, many of the studies appear to becontradictory (summarized in Table 3). Cardiac-specific transgenicmice expressing a dominant negative form of p38α were generatedand analyzed by two independent groups (Braz et al., 2003; Zhang etal., 2003a). Zhang et al. (2003a) reported no basal phenotype in dn-p38α transgenics. In contrast, Braz et al. (2003) found that dn-p38αtransgenics developed concentric hypertrophy associated with a fallin cardiac function and elevated fetal gene expression (ANP and BNP),with the majority of mice dying prematurely from cardiomyopathy by8 months of age. Both groups subjected the dn-p38α transgenics topressure overload and reported a significant increase in heart size.Zhang et al. reported a hypertrophic response (to pressure overload)

in the dn-p38α transgenics similar to control animals but, interest-ingly, the transgenics had significantly less fibrosis (Zhang et al.,2003a). In contrast, Braz et al. (2003) reported an exaggeratedhypertrophic response in dn-p38α transgenics compared withcontrols in response to pressure overload or 14 day minipumpinfusions of phenylephrine, Ang II and isoproterenol. Finally,cardiac-specific p38α knockout mice displayed normal cardiacstructure and function under basal conditions (Nishida et al., 2004).In response to pressure overload, knockout mice developed a similardegree of cardiac hypertrophy to controls, but displayed greatercardiac dysfunction, more fibrosis and apoptosis (Nishida et al., 2004).The authors concluded that p38α plays a critical role in protecting theheart in a setting of pressure overload.

Cardiac-specific dn-p38β transgenic mice had no cardiac hypertro-phy under basal conditions but seemed to have reduced systolicfunction (Zhang et al., 2003a). The hypertrophic response to pressureoverload was not different from that observed in non-transgenic mice,though the dn-p38β transgenics were reported to display less fibrosis(Zhang et al., 2003a).

MEK3 and MEK6 are regulators of p38-MAPK (Fig 5). Under basalconditions dnMEK3 and dnMEK6 transgenic mice developed patho-logical hypertrophy by 2 and 8 months of age, respectively. Bothmodels displayed cardiac dysfunction, and fibrosis was also reportedin dnMEK3 transgenics at 4 months of age. The majority of dnMEK3mice died by 8 months of age due to cardiomyopathy (Braz et al.,2003). In response to pressure overload, dnMEK3 and dnMEK6transgenic mice displayed an exacerbated cardiac hypertrophicresponse, increased fibrosis and depressed cardiac function, similarto the observations in dn-p38α transgenic mice (Braz et al., 2003).

Activation of p38-MAPK in either MEK3 or MEK6 transgenic heartsunder baseline conditions led to the increased expression of the fetalgene program, substantial induction of interstitial fibrosis, and loss ofcontractility (Liaoet al., 2001). Both transgenicmousemodels developedheart failure, although this was not associated with hypertrophy ofcardiacmyocytes (Liao et al., 2001). In this set of studies, p38-MAPKdoesnot appear to promote hypertrophy, but seems to contribute to fibrosis,loss of contractility and the development of dilated cardiomyopathy.

Explanations for the possible discrepancies between many of thesemodels (see Table 3) may be attributed to the generation of transgenicmice on different genetic backgrounds (Braz et al., 2003; Zhang et al.,2003a), gender differences (Liu et al., 2006) (discussed in detail in


Section 7), p38-MAPK having an anti-apoptotic function that isindependent of kinase activity or a biphasic dose response curve top38α-MAPK (Muslin, 2008), as well as distinct roles of p38α and β thatmaybedifferentially regulatedbyMEK3andMEK6(Wanget al., 1998a).

3.2.3.5. Protein kinases. Extracellular stimuli such as pressure overloadactivate PKC and PKD via GPCRs to trigger hypertrophic responses(Dorn & Force, 2005; Harrison et al., 2006) (Fig 5).

3.2.3.5.1. PKC. PKC is considered a critical signal transducerdownstream of Gq. There are at least 12 isoforms of PKC and at least4 (α, β, δ, and ε) have been implicated in the induction of cardiachypertrophy (see Dorn & Force, 2005). PKCα and PKCβ areconventional Ca2+-dependent isoforms whereas PKCε and PKCδ arenovel Ca2+-independent isoforms (Mackay & Mochly-Rosen, 2001;Sabri & Steinberg, 2003). Mice null for PKCα, β, δ, or ε had no obviouscardiac phenotype under basal conditions (see Dorn & Force, 2005),however it has been suggested that the role of specific PKC isoformsmay be masked by compensatory signaling by other PKC isoforms(Dorn & Force, 2005). Cardiac-specific PKCβ transgenic mice devel-oped cardiac hypertrophy associated with cardiac dysfunction,fibrosis and premature death (Bowman et al., 1997; Wakasaki et al.,1997; Chen et al., 2001a), but knockout mice displayed a typicalhypertrophic response to a GPCR agonist (PE) or aortic-banding(Roman et al., 2001). Thus, it appears that PKCβ is not required for thepathological hypertrophic response. Cardiac-specific transgenic miceover-expressing PKCε or PKCδ displayed mild concentric hypertrophywith a physiological phenotype (no evidence of fibrosis, and normalcardiac function) (Takeishi et al., 2000; Chen et al., 2001a). However,in response to a cardiac insult (ischemia-induced damage), PKCε hada protective role, whereas activation of PKCδ exacerbated the damage(Chen et al., 2001a). PKCα appears to be critical for regulating cardiaccontractility but not cardiac hypertrophy (Braz et al., 2002; Hahn etal., 2003; Braz et al., 2004). Transgenic mice with over-expression ofPKCα had diminished cardiac contractility while PKCα−/− mice hadimproved cardiac contractility (Braz et al., 2004). Furthermore,inhibition of PKCα activity in a model of pathological hypertrophy(Gαq transgenic mice) improved cardiac contractility, whereasactivation of PKCα resulted in a lethal cardiomyopathy (Hahn et al.,2003). There were no apparent effects on heart size under basalconditions or in response to cardiac stress (e.g. pressure overload)with the PKCα mouse models.

3.2.3.5.2. PKD. Cardiac-specific transgenic mice expressing aconstitutively active form of PKD1 developed pathological hypertro-phy and died prematurely (Harrison et al., 2006). In contrast, micewith conditional cardiac-specific deletion of PKD1 had no phenotypeunder basal conditions but displayed a blunted hypertrophic responseto various pathological models (pressure overload, Ang II-dependenthypertrophy and isoproterenol-dependent hypertrophy) which wasassociated with better cardiac function, less fibrosis, and less fetalgene activation compared to control mice (Fielitz et al., 2008).

3.2.4. Calcium signalingEach heartbeat is associated with entry of calcium into cardiac

myocytes. Calcium is central to the control of contractile function andcardiac growth. Calcium/calmodulin is an important second messen-ger for GPCR agonists and biomechanical stress (Frey et al., 2000; Aoki& Izumo, 2001; Sugden, 2001). The best described calcium-dependentsignaling proteins include calcineurin and calcium/calmodulin-de-pendent protein kinases (CaMKs). Calcineurin is a serine–threoninephosphatase that consists of a catalytic A subunit and a regulatory Bsubunit. Two regulatory subunit genes (B1, B2) have been identified,and three genes encode the A catalytic subunit, calcineurinAα (CnAα),calcineurinAβ (CnAβ) and calcineurinAγ (CnAγ). Only the α and βgenes have been shown to be expressed in human, mouse and rathearts (Klee et al., 1998; Molkentin & Dorn, 2001). Calcineurindephosphorylates nuclear factor of activated T cells (NFAT) transcrip-

tion factors which promotes nuclear translocation and activation ofgene transcription (Fig. 5).

Following stimulation with GPCR hypertrophic agonists (Ang IIand PE) in cultured rat neonatal cardiac myocytes, calcineurinenzymatic activity, CnAβ (but not CnAα or CnAγ) mRNA and proteinlevels were increased (Taigen et al., 2000). Calcineurin activity wasalso increased in hypertrophied and failing hearts from humanpatients (Haq et al., 2001), and human failing heart ventricularmuscle exposed to ET-1, Ang II and urotensin II (Li et al., 2005).Furthermore, calcineurin activity was upregulated in hypertrophiedhearts following aortic-banding in rodents (Shimoyama et al., 1999;Lim et al., 2000; De Windt et al., 2001; Zou et al., 2001; Saito et al.,2003). Finally, transgenic mice expressing an activated form ofcalcineurin in the heart developed profound cardiac hypertrophywhich rapidly progressed to dilated cardiomyopathy, with extensiveinterstitial fibrosis, congestive heart failure and sudden death, oftenby 3 months of age (Molkentin et al., 1998). Taken together, thesestudies imply that elevated calcineurin induces pathological cardiachypertrophy.

Consistent with the idea that calcineurin/NFAT coupling inducespathological cardiac growth, when NFAT-luciferase reporter micewere subjected to both physiological stimuli (exercise training,growth hormone-IGF1 infusion) and pathological stimuli (pressureoverload, myocardial infarction), NFAT luciferase reporter activitywasupregulated in both pathological models but not in the physiologicalmodels (Wilkins et al., 2004). In addition, transgenic mice withtargeted inactivation of calcineurin Aβ displayed an impairedhypertrophic response to pressure overload and infusion of GPCRagonists (Bueno et al., 2002), and cardiac hypertrophy in transgenicmice expressing a dominant negative form of calcineurin A displayeda blunted hypertrophic response to pressure overload compared towildtypemice (Zou et al., 2001). Finally, pharmacological inhibition ofcalcineurin activity prevented cardiac hypertrophy in constitutivelyactive calcineurin A transgenic mice (Molkentin et al., 1998).

As noted previously, calcineurin is considered to regulate thepathological hypertrophic response via dephosphorylation of NFAT(Fig. 5)(Olson & Williams, 2000). NFAT translocates to the nucleus,where it associates with other transcription factors such as GATA4 andmyocyte enhancer factor 2 (MEF2), to regulate the expression ofcardiac genes (Wilkins et al., 2002; Frey & Olson, 2003). In support ofthis, Molkentin et al. (1998) showed that cardiac-specific transgenicmice expressing a constitutively activate mutant form (nuclearlocalized) of NFAT3 developed cardiac hypertrophy and heart failure,whereas expression of the wildtype protein did not lead tohypertrophy (Molkentin et al., 1998).

The contribution of calcineurin in mediating cardiac hypertrophyhas also been examined utilizing myocyte-enriched calcineurin-interacting protein 1 (MCIP1) transgenic mice. MCIP is able to inhibitcalcineurin signaling by binding directly to the catalytic subunit(CnA), which inactivates its ability to dephosphorylate NFAT andMEF2 (Fig. 5). Forced over-expression of MCIP1 selectively in theheart of transgenic mice was able to attenuate hypertrophy andprevent progression to dilated cardiomyopathy in response to variouspathological stimuli, including aortic-banding, transgenic expressionof CnA, and the β-adrenergic receptor agonist isoproterenol (Rother-mel et al., 2001; Hill et al., 2002). This is consistent with the idea thatenhanced calcineurin signaling mediates pathological growth.Though, interestingly, transgenic expression of MCIP also inhibitedexercise-induced hypertrophy (voluntary runningwheel) (Rothermelet al., 2001). Studies utilizing MCIP1 null mice have also beencomplicated to interpret. MCIP−/− mice had a normal cardiacphenotype under basal conditions, displayed an exaggerated hyper-trophic response to transgenic expression of CnA, but a bluntedhypertrophic response to pressure overload and adrenergic stimula-tion (isoproterenol) (Vega et al., 2003). The authors concluded thatMCIP1 may have a dual role in hypertrophic signaling, acting as a


suppressor or activator, depending on the initiating stimulus (Vega etal., 2003).

Calcium/calmodulin-dependent protein kinase II (CaMKII) is aserine/threonine protein kinase that has been implicated in cardiachypertrophy and heart failure. Upregulation of CaMKII has beenreported in hearts of patients and animal models with heart failure(Hoch et al., 1999; Kirchhefer et al., 1999; Bossuyt et al., 2008). Fourisoforms (α, β, δ and γ) of CaMKII exist, which are encoded byseparate genes. CaMKIIδ is the predominant isoform in the heart andhas distinct splice variants (δA, δB, δC); γ is also expressed in the heart(Tobimatsu & Fujisawa, 1989; Edman & Schulman, 1994; Srinivasan etal., 1994; Baltas et al., 1995; Mayer et al., 1995; Ramirez et al., 1997b).

Transgenic studies have provided evidence for the involvement ofCaMKII in pathological cardiac hypertrophy. Over-expression ofCaMKIIδB (nuclear isoform) in the mouse heart induced cardiachypertrophy and dilated cardiomyopathy (Zhang et al., 2002b).Similarly, cardiac-specific transgenic mice over-expressing CaMKIIδC(cytoplasmic isoform) developed cardiac hypertrophy (with mildfibrosis), dilated cardiomyopathy and heart failure (lung congestion,atrial dilation and severe edema) (Zhang et al., 2003b). Both CaMKIIδBand CaMKIIδC transgenic expression induced a genetic programassociated with hypertrophy and heart failure (i.e., ANP, β-MHC andα-skeletal actin mRNA were increased, α-MHC, SERCA2a andphospholamban (PLB) were decreased). Further supporting thisrole, a genetic mouse model of CaMKII inhibition prevented cardiacdilation and dysfunction resulting from myocardial infarction and β-AR stimulation (Zhang et al., 2005). Under basal conditions, thesetransgenic mice had a stable cardiac phenotype (no hypertrophy),normal cardiac development and function (Zhang et al., 2005). Morerecently, CaMKIIδ-null mice (generated using a Cre-loxP approach)were shown to be protected against hypertrophy and fibrosis inresponse to pressure overload caused by aortic-constriction (Backs etal., 2009). Fetal gene expression (ANP, BNP, β-MHC) was alsoattenuated in this model. In contrast, germline ablation of CaMKIIδdid not affect the development of hypertrophy following pressureoverload induced by two weeks of aortic constriction, which may beexplained by the upregulation of CaMKIIγ compensating for the loss ofCaMKIIδ (Ling et al., 2009). However, after long term aortic banding(6 weeks), cardiac function was maintained, enlargement of the heartwas attenuated, pulmonary congestion and lung edema werereduced, and survival rates improved in the knockout modelcompared to wildtype mice, suggesting that CaMKIIδ deletion inhibitsthe development of heart failure induced by long term pressureoverload (Ling et al., 2009).

CaMKII signaling is thought to exert its effect on cardiac hypertrophyby causing phosphorylation of class II histone deacetylase 4 (HDAC4),which in turn dissociates from the MEF2 transcription factor, and istranslocated from the nucleus to the cytoplasm. This causes activation ofMEF2which is sufficient to promote pathological hypertrophy (Backs &Olson, 2006; Backs et al., 2006; Kim et al., 2008a). In further support ofthis role, CaMKIIδ-nullmice demonstrated a clear reductionofHDAC4 inventricular lysates (Backs et al., 2009).

3.3. Complexities and future work in relation to signaling cascades

The most frequently used animal models of pathological hyper-trophy (e.g. aortic-banding, hypertension) represent a chronicpressure load that results in concentric hypertrophy. In contrast,models of physiological hypertrophy (e.g. treadmill, voluntary free-wheel, swimming) represent an intermittent volume load that resultsin eccentric hypertrophy. Thus, it has been argued that differences inphenotypes and signaling observed in models of pathological andphysiological hypertrophy may be a consequence of the duration ofthe insult (constant versus intermittent) or type of load (volumeversus pressure). These issues have been addressed to some extent bythe following studies: i) mouse hearts subjected to intermittent

pressure overload displayed pathological features including diastolicdysfunction, reduced capillary density, histological and cellularabnormalities, and a fall in SERCA2a (Perrino et al., 2006); ii)cardiac-specific chronic transgenic expression of IGF1R or caPI3Kwas associated with a physiological phenotype that did not progressto a pathological phenotype (Shioi et al., 2000; McMullen et al.,2004b); iii) transgenic mice with enhanced ERK5 activation devel-oped eccentric hypertrophy that progressed to dilated cardiomyop-athy (Nicol et al., 2001), iv) a pathological model of eccentrichypertrophy (myocardial infarction) and a physiological model ofeccentric hypertrophy (voluntary exercise wheel) in rats wereassociated with differential regulation of signaling proteins (Gosselinet al., 2006). Together these data suggest that it is not whether astimulus is chronic or intermittent, or whether the initiatinghypertrophic stimuli represent a pressure or volume overload thatdetermines whether the resultant cardiac hypertrophy is pathologicalor physiological.

Further studies are required to determine whether postnatalcardiac growth, pregnancy-induced growth, and exercise-inducedhypertrophy are mediated by similar molecular mechanisms. PI3K(p110α) is critical for postnatal heart growth and exercise-inducedgrowth (Shioi et al., 2000; McMullen et al., 2003); whereas the Gαqsignaling pathway was critical for pathological growth but notpostnatal heart growth (Wettschureck et al., 2001). Signalingcascades implicated in mediating pregnancy-induced heart growthhave not been extensively studied but may be coupled to Kv4.3, c-Src,cGMP and estrogen receptors. Consistent with the classification ofpregnancy-induced growth as physiological, pregnancy does nottrigger changes in classic markers of pathological hypertrophyincluding β-MHC or ANP (Eghbali et al., 2005; Eghbali et al., 2006).

Examination of signaling pathways that specifically induce anddifferentiate between eccentric or concentric hypertrophy have notbeen clearly defined. Patients and animal models with eccentrichypertrophy have a particularly poor prognosis (Berenji et al., 2005).An understanding of eccentric hypertrophy at the molecular level islikely to provide important insight into why compensated hypertro-phy can progress to heart failure. It will also be important todifferentiate between physiological eccentric hypertrophy and path-ological eccentric hypertrophy. For instance, hypertrophy in responseto isotonic exercise is classified as eccentric but is quite different toeccentric hypertrophy associated with decompensation of the heart.Furthermore, pregnancy-induced hypertrophy due to volume over-load is not associated with recapitulation of the fetal gene programwhereas a similar volume overload in response to aortocaval shuntcaused an increase in ANP and β-MHC gene expression (Sopontam-marak et al., 2005; Eghbali et al., 2006). Gp130-mediated signalscontribute to the development of eccentric hypertrophy. Both CT-1and LIF cause elongation of myocytes due to assembly of sarcomericunits in series rather than in parallel (Wollert et al., 1996). But aspreviously noted, activation of this pathway is considered protective.In contrast, MEK5 induces eccentric hypertrophy and heart failurewith no report of intervening concentric hypertrophy (Nicol et al.,2001). An intact sensing apparatus that can detect changes infunctional load appears essential in the compensatory response topathological insults. Mutations or deletions of sensor proteins havebeen associated with dilated cardiomyopathy/eccentric hypertrophycharacterized by ventricular chamber dilation, fibrosis and heartfailure. Integrins (heterodimeric transmembrane receptors), link theextracellular matrix to the intracellular cytoskeleton. Interactingproteins/downstream effectors of integrins (e.g. melusin, focaladhesion kinase (FAK), small GTPases) as well as proteins at thelevel of the Z-disc within sarcomeres (e.g. muscle LIM protein) areconsidered biomechanical stretch sensors. Control mice typicallydevelop concentric hypertrophy in response to pressure overload(aortic banding) that may later progress to eccentric hypertrophy andheart failure. In contrast, mice lacking stretch-sensor proteins (e.g. β-


integrin, melusin, FAK, and muscle LIM protein) developed eccentrichypertrophy and cardiac dysfunction under basal conditions or inresponse to pressure overload, i.e. no intermediate concentrichypertrophy (Arber et al., 1997; Shai et al., 2002; Brancaccio et al.,2003; Peng et al., 2006). On the other hand, melusin expression isincreased during compensated hypertrophy induced by pressureoverload, and over-expression of melusin in transgenic miceprolonged concentric hypertrophy and protected against the transi-tion to eccentric hypertrophy and failure (De Acetis et al., 2005).

4. Molecular mechanisms associated with structuralfeatures of pathological and physiological hypertrophy

4.1. Molecular mechanisms associated with protein synthesis

An essential feature of both physiological and pathological cardiachypertrophy is increased protein synthesis. Ribosomal S6 kinases (S6Ks:S6K1 and S6K2) are considered critical regulators of protein synthesis inresponse to hypertrophic stimuli. Activation of S6K1 was increased inhearts of transgenic mouse models of physiological hypertrophy (micewith increased activation of the IGF1-PI3K(p110α) pathway) andpathological hypertrophy (pressure overload) (Shioi et al., 2000; Shioiet al., 2003; McMullen et al., 2004a,b). Rapamycin, an inhibitor of themammalian target of rapamycin (mTOR; a proximal effector of S6Ks)inhibited S6K1 and attenuated and regressed pathological hypertrophyinduced by pressure overload (Shioi et al., 2003; McMullen et al.,2004a). Unexpectedly, deletion of S6Ks (utilizing global S6K knockoutmice) did not attenuate cardiac hypertrophy induced by exercisetraining, transgenic expression of IGF1R/caPI3K or pressure overload(McMullen et al., 2004c). Together, these data suggest that S6Ks are notessential for the induction of physiological or pathological cardiachypertrophy, or that other proteins were upregulated in the knockoutmodels.

4.2. Molecular mechanisms associated with sarcomeric organization

The formation of sarcomeres is a complex process involving thesynthesis of numerous proteins (Zak, 1984; Vigoreaux, 1994). Theseproteins aggregate into filaments, which are organized into specificthree-dimensional arrays and aligned with other contractile elementsalready present in the cardiac myocyte (Zak, 1984; Sanger et al., 2000).Cardiac hypertrophy facilitates the increased workload (e.g. strain ofpressure or volume overload) by increasing contractile capacity.Organization of sarcomeres, and thereby an increase in the contractileunits, is an essential component to maximize force generation. Thetransition from pathological hypertrophy to heart failure has beenassociated with loss of contractile filaments in the presence ofmicrotubule densification and desmin disorganization, and loss ofproteins of the sarcomeric skeleton (titin, α-actin, myomesin) (Tsutsuiet al., 1993;Hein et al., 2000;Hamdani et al., 2008).Defects ormutationsof sarcomeric proteins, including cardiac troponin I or T, β-MHC, α-MHC, myosin light chain (MLC), α-tropomyosin, titin, and actin, havebeen associated with familial hypertrophic cardiomyopathy in humans(Margulies & Houser, 2004; Lind et al., 2006; Morimoto, 2008;Tsoutsman et al., 2008). Signaling proteins and regulators of geneexpression that have been implicated in sarcomere organization includeRac1, RhoA (Aoki et al., 1998;Hoshijima et al., 1998; Pracyk et al., 1998),FAK and p130Cas (substrates for the non-receptor tyrosine kinase Src)(Kovacic-Milivojevic et al., 2001), multiple kinases (see Seguchi et al.,2007; Solaro 2008), Nkx2.5/Csx (Kasahara et al., 2003), and HDAC4(Gupta et al., 2008).

4.3. Molecular mechanisms associated with fibrosis

Cardiac fibrosis is a common feature in animal models ofpathological hypertrophy and patients with advanced heart failure.

In response to a pathological insult, cardiac fibroblasts and extracel-lular matrix proteins accumulate disproportionately and excessively.This leads to mechanical stiffness which contributes to diastolicdysfunction and can progress to systolic dysfunction (Weber & Brilla,1991; Villarreal & Dillmann, 1992; Weber et al., 1993; Brower et al.,2006). It is recognized that anti-fibrotic therapies may be useful inimproving cardiac function of the diseased heart. However, thedevelopment of such therapies has been limited by an incompleteunderstanding of the source of fibroblasts and mechanisms respon-sible for the induction of excessive collagen accumulation. Tradition-ally, adult fibroblasts are considered to be derived directly fromembryonic mesenchymal stem cells and to increase in number in asetting of pathological stress due to proliferation of residentfibroblasts (Weber & Brilla, 1991; Maric et al., 1997; Weber, 1997;Lang and Fekete 2001). More recently, it has been demonstrated thatbone marrow derived fibroblasts, as well as endothelial cell derivedfibroblasts (via endothelial–mesenchymal transition) contribute tothe population of cardiac fibroblasts (Zeisberg et al., 2007).

Genetic mouse models have provided some insight in relation tothe molecular mechanisms responsible of fibrosis associated withpathological hypertrophy. Triggers, receptors, signaling proteins, andtranscription factors implicated in the development of cardiac fibrosisinclude: Ang II, AT1 receptor, TGF-β, tumor necrosis factor (TNF)-α, Gproteins (Gαq, Gαs), PKCβ2, RhoA, calcineurin, calsequestrin, NFATs,Csx/Nkx2.5, and serum response factor (see Manabe et al., 2002;Gunasinghe & Spinale, 2004; Rosenkranz, 2004).

TGF-β1 is probably the best describedmediator of cardiacfibrosis. Intheheart, TGF-β1 is secreted by cardiacfibroblasts in response to stimulisuch asAng II (Khan& Sheppard, 2006). The effects of TGF-β1 on cardiacfibrosis appear to be mediated in part via Smads and TGF-β-activatedkinase-1 (TAK1) leading to increased transcription of extracellularmatrix proteins (Rosenkranz, 2004; Khan & Sheppard, 2006). Trans-genicmice over-expressing TGF-β1 developed cardiac hypertrophy thatwas associated with interstitial fibrosis and increased myocyte size(Rosenkranz et al., 2002). In contrast, heterozygousTGF-β1+/−deficientmice displayed less cardiac fibrosis with aging (Brooks & Conrad, 2000).TGF-β1 was also responsible for endothelial cells undergoing endothe-lial–mesenchymal transition and the induction of increased fibrosis in asetting of pathological hypertrophy induced by pressure overload(Zeisberg et al., 2007). Furthermore, inhibition of TGF-β1 withrecombinant bone morphogenic protein-7 (member of the TGF-βsuperfamily of growth factors) was able to inhibit endothelial–mesenchymal transition and fibrosis in mice with pressure overload-induced hypertrophy (Zeisberg et al., 2007).

Myocyte death by apoptosis or necrosis is typically observed inparallel with the onset of fibrosis. Debate remains as to whetherfibrosis is simply a non-specific response to myocyte loss or whetherthe release of secretory factors from myocytes promote or inhibitcollagen synthesis also plays a significant role (Benjamin et al., 1989).It was shown that rat cardiac myocytes induce secretion of active TGF-β in the presence of Ang II and that a paracrine action of TGF-βinduced cytokines in fibroblasts to promote collagen synthesis (Sarkaret al., 2004).

4.4. Molecular mechanisms associated with cell death

Pathological hypertrophy is typically associatedwith increased celldeath (apoptosis and necrosis) whereas physiological hypertrophy isnot. Thus, differential activation of pro-survival and pro-death signalsis likely to be an important factor that contributes to the distinctphenotypes of these two forms of heart growth. Low levels ofapoptosis were sufficient to induce heart failure in mice, andinhibition of cell death with a polycaspase inhibitor largely preventedthe heart failure phenotype (Wencker et al., 2003). In another study,inhibition of apoptosis with a caspase inhibitor improved cardiac

Fig. 8. Alterations in substrate utilization in pathological and physiological cardiachypertrophy. Pathological hypertrophy is associated with a switch from fatty acid toglucose utilization, although glucose metabolism also decreases with the progression toheart failure. In contrast, physiological hypertrophy is associated with enhanced ratesof fatty acid and glucose oxidation.


function and prevented mortality in pregnant cardiac-specific Gαqtransgenic mice (Hayakawa et al., 2003).

Growth factors (e.g. IGF1), and cytokines (e.g. CT-1) have anti-apoptotic effects, in part, via PI3K and/or ERK signaling (Parrizas et al.,1997; Sheng et al., 1997; Haunstetter and Izumo 1998; Kang et al.,2002). In contrast, signaling via Gαq or Gαs in transgenic mice wasshown to promote cardiac myocyte apoptosis (Adams et al., 1998;Geng et al., 1999). Calcineurin has been reported to have both pro-

Fig. 9. Overview of energy metabolism in cardiac myocytes. Circulating fatty acids, glucosFollowing uptake into cardiac myocytes, fatty acids are transported to the mitochondria btricarboxylic acid (TCA) cycle and oxidative phosphorylation. Glucose and lactate are conoxidation pathways. Asterisks denote proteins and processes that can induce cardiac hypertrhypoxia inducible factor 1α, NADPH: nicotinamide adenine dinucleotide phosphate, PPAR:

and anti-apoptotic effects (DeWindt et al., 2000; Saito et al., 2000; Puet al., 2003). JNK, p38-MAPK, and loss of gp130 have been associatedwith increased apoptosis in cardiac myocytes (Wang et al., 1998a;Hirota et al., 1999; Kang et al., 2002).

Rats with pathological hypertrophy (Dahl salt sensitive rats on ahigh salt diet) were more sensitive to apoptotic stimulation thancardiac myocytes from rats with exercise-induced physiologicalhypertrophy (treadmill). The physiological hypertrophic model wasassociated with changes in Bcl-2 family members and caspasesfavoring survival, whereas the pathological model was associatedwith changes in mitochondrion- and death receptor-mediated path-ways (e.g. a decreased Bcl-xL/Bax ratio, increase in Fas) that havepreviously been associated with pathological hypertrophy and heartfailure (Kang et al., 2004).

4.4.1. AutophagyAutophagy is the process by which cells degrade and recycle aged

proteins and damaged organelles. Inhibition of autophagy triggersapoptosis, indicating that autophagy plays a key role in cell survival(Boya et al., 2005). Autophagy is upregulated in numerous models ofpathological hypertrophy and in failing hearts (see Nishida et al.,2008; Nishida et al., 2009). This may be a protective mechanism,preventing the accumulation of cytoplasmic components that disruptcardiac function (Nishida et al., 2009). Little is known about the role ofautophagy in settings of physiological cardiac hypertrophy, howeverautophagy is upregulated by exercise and appears to be important foramino acid turnover and protein synthesis in skeletal muscle postexercise (see Gottlieb et al., 2009).

e and lactate are the main fuel sources utilized by cardiac myocytes to generate ATP.y carnitine palmitoyltransferase I (CPTI) and II (CPTII) for β-oxidation, entry into theverted to pyruvate before entering the mitochondria and converging with fatty acidophy when altered or defective. ATP: adenosine triphosphate, CoA: coenzyme A, HIF1α:peroxisome proliferator-activated receptor, ROS: reactive oxygen species.


5. Molecular mechanisms associated with differences inenergy metabolism in pathological and physiological hypertrophy

As described earlier, pathological and physiological hypertrophyare associated with distinct metabolic profiles. Substrate utilization inpathological hypertrophy resembles that of the fetal heart (decreasedfatty acid oxidation, increased glycolysis), while physiologicalhypertrophy induced by exercise training is associated with enhancedfatty acid and glucose oxidation (see Lehman & Kelly, 2002; Fig. 8).Whether alterations in energymetabolism are a cause or consequenceof cardiac hypertrophy and failure is controversial, however there is agrowing body of evidence to suggest that switches in substrateutilization and other alterations in energy metabolism do contributeto the development of pathological hypertrophy and failure. Theaccumulation of lipids in cardiac myocytes is deleterious and can leadto pathological hypertrophy and heart failure, although the mechan-isms responsible for lipotoxic cardiomyopathy are still unknown.Reactive oxygen species (ROS), a by-product of mitochondrial energymetabolism, may also induce hypertrophy in pathological settings(Fig. 9).

5.1. Peroxisome proliferator-activated receptors (PPARs)

The PPAR family of transcription factors are key metabolicregulators that have been implicated in the development of cardiachypertrophy (see Robinson & Grieve, 2009 for review). PPARα is anuclear receptor that regulates lipid metabolism by increasingtranscription of genes involved in fatty acid oxidation, such asmuscle-type carnitine palmitoyltransferase 1 (mCPT-1) and mediumchain acyl coenzyme A dehydrogenase (MCAD) (Fig. 9) (see Barger &Kelly, 2000). PPARα expression was elevated in hearts of trained rats(Rimbaud et al., 2009) and downregulated in several models ofpathological hypertrophy (see Barger et al., 2000; Lehman & Kelly,2002; Akki et al., 2008) as well as in the fetal heart (Sack et al., 1997).Transgenic mice deficient for PPARα developed greater hypertrophyand had worse cardiac function compared to wildtype mice whensubjected to pressure overload (Smeets et al., 2008). In addition,administration of a PPARα agonist attenuated hypertrophy inducedby aldosterone treatment in mice (Lebrasseur et al., 2007) and in tworat models of pathological hypertrophy (Ichihara et al., 2006; Linz etal., 2009). These studies suggest that downregulation of PPARα (andtherefore fatty acid oxidation) contributes to the development ofpathological hypertrophy, although a study in cardiac-specifictransgenic mice has demonstrated that enhanced PPARα proteinexpression can also induce hypertrophy and cardiac dysfunction(Finck et al., 2003).

PPARα is a target of ERK1/2 (Barger et al., 2000), a signalingprotein which is activated in settings of pathological cardiachypertrophy (see Section 3.2.3.1). Deactivation of PPARα by ERK1/2was responsible for the reduction in fatty acid oxidation observed incardiacmyocytes stimulated with the hypertrophic agonist PE (Bargeret al., 2000), indicating that signaling pathways involved in thedevelopment of cardiac hypertrophy can also exert changes in cellularmetabolism.

The role of PPARγ in the development of cardiac hypertrophy isless clear. Several studies suggest that PPARγ is protective, as micelacking PPARγ in the heart developed cardiac hypertrophy anddysfunction (Ding et al., 2007), and treatment with a PPARγ agonistreduced cardiac remodeling and fibrosis in a rat model of hyperten-sion (Henderson et al., 2007). However, cardiac-specific over-expression of PPARγ in mice also resulted in cardiac dysfunction(Son et al., 2007), indicating that PPARγ activation is not alwaysprotective (Fig. 9). A recent study demonstrated that transgenic micewith enhanced PPARγ activity (due to elevated levels of ventricularhypoxia-inducible factor 1α, HIF1α) developed concentric hypertro-phy which progressed to dilated cardiomyopathy at around 5–

6 months of age (Fig. 9) (Krishnan et al., 2009). This was attributedto PPARγ-dependent lipid accumulation and cardiac myocyte apo-ptosis. HIF1α is a key regulator of genes involved in glycolyticmetabolism and was found to be highly expressed in ventricularbiopsies from patients with hypertrophic cardiomyopathy. HIF1αwasalso highly expressed in a mouse model of pathological hypertrophyinduced by pressure overload, but not in physiological hypertrophyinduced by exercise training. This study provides strong evidence thata switch from fatty acid to glycolytic metabolism leads to pathologicalhypertrophy and is ultimately detrimental for cardiac function.

5.2. Lipid accumulation and pathological hypertrophy

Lipid accumulation appears to act as a trigger for cardiac myocytehypertrophy (Chiu et al., 2001) and is evident in the failing humanheart (Sharma et al., 2004), however mechanisms responsible forlipotoxic cardiomyopathy are unclear (see McGavock et al., 2006 andPark et al., 2007 for reviews). Lipid accumulation can result fromalterations in fatty acid uptake, transport or oxidation. For example,carnitine is responsible for transporting long-chain fatty acids fromthe cytosol into the mitochondria for subsequent β-oxidation (Fig. 9).Carnitine deficiency impairs fatty acid oxidation and has beenassociated with the development of left ventricular hypertrophy andcardiomyopathy in humans (Koizumi et al., 1999). Mice with systemiccarnitine deficiency (juvenile visceral steatosis (JVS) mice) displayedsignificant cardiac hypertrophy at eight weeks of age (Horiuchi et al.,1993; Kuwajima et al., 1998) and were more susceptible to pressureoverload (Takahashi et al., 2007). Treatment with carnitine attenu-ated the basal hypertrophic phenotype in JVS mice (Horiuchi et al.,1993), and improved cardiac function in JVS mice subjected topressure overload (Takahashi et al., 2007). Furthermore, limitingdietary lipid intake attenuated hypertrophy in JVS mice and this wasassociated with reduced triglyceride accumulation in the ventricles(Jalil et al., 2006).

Enhanced fatty acid uptake (e.g. due to excess dietary lipids, asoccurs in obesity) has also been linked with the development ofpathological hypertrophy (Kankaanpaa et al., 2006; Koonen et al.,2007) and may play a role in the development of diabeticcardiomyopathy (see Carley & Severson, 2005), although high-fatfeeding attenuated hypertrophy in rats with hypertension (Okere etal., 2005).

5.3. Reactive oxygen species(ROS)/oxidative stress and pathological hypertrophy

ROS are a natural by-product of mitochondrial energy production(Fig. 9). Oxidative stress occurs when ROS production outweighs theantioxidant capabilities of the cell, and has been implicated in thepathogenesis of cardiac hypertrophy and heart failure (McMurrayet al., 1993). Hypertrophic stimuli, such as Ang II, ET-1 andcatecholamines, are capable of stimulating ROS production in cardiacmyocytes (Liu et al., 2004; Laskowski et al., 2006). Defective NADPHoxidase activity is another source of ROS that has been implicated inthe development of pathological hypertrophy (see Murdoch et al.,2006). A study in transgenic mice demonstrated that NADPH oxidaseplays an important role in the development of cardiac hypertrophy, asmice deficient for the gp91phox subunit of NADPH oxidase wereprotected from developing pathological hypertrophy induced bychronic infusion of Ang II (Bendall et al., 2002).

ROS production also increases during exercise although thisappears to have a preconditioning effect, reducing susceptibility tooxidative stress-related disorders (see Radak et al., 2008). Exercise-induced ROS production is much lower in the heart compared withliver and skeletal muscle (Traverse et al., 2006). Thus it seems unlikelythat ROS play a role in the development of physiological hypertrophy.

Fig. 10. Venn diagram showing the shared and distinct gene clusters (as determinedfrommicroarray analysis) that have been shown to be associated with pathological andphysiological hypertrophy. HSF1 is a heat shock protein transcription factor that hasrecently been shown to be involved in physiological hypertrophy. Data collected from(Kong et al., 2005; Mirotsou et al., 2006; Dorn 2007).


5.4. Changes in energy metabolismassociated with physiological cardiac hypertrophy

There are clear differences in energy metabolism betweenpathological and physiological hypertrophy. While pathologicalhypertrophy is typically associated with a switch from fatty acid toglucose utilization, physiological hypertrophy is accompanied byenhanced rates of fatty acid and glucose oxidation. This has beendemonstrated in numerous animal models, as well as in humans. Forexample, the expression of genes encoding enzymes involved in fattyacid oxidation (i.e. PPARα, mCPT-1, and MCAD) was significantlyincreased in the hearts of trained rats but not hypertensive rats,despite a similar degree of hypertrophy (Rimbaud et al., 2009). Inanother study, phosphofructokinase and lactate dehydrogenase, keyregulators of glycolytic metabolism, were upregulated in pathologicalhypertrophy induced by hypertension but not in physiologicalhypertrophy induced by exercise training (Iemitsu et al., 2003). Asmentioned previously, HIF1α (a key regulator of glycolytic metabo-lism) was elevated in mice and human patients with pathologicalhypertrophy, but not in a mouse model of physiological hypertrophy(Fig. 9) (Krishnan et al., 2009). Rats with exercise-induced hypertro-phy had lower rates of glycolysis compared to sedentary controls,while glucose and palmitate (i.e. fatty acid) oxidation increased by45% and 50–65%, respectively (Burelle et al., 2004). The enhancedoxidative capacity of hearts that have undergone physiologicalhypertrophy suggests a protected phenotype.

6. Characteristic gene expression changesassociated with pathological and physiological hypertrophy

Intracellular signaling pathways are coupled with transcriptionfactors in the nucleus to regulate the long-term alterations in geneexpression that are associated with cardiac hypertrophy. Classically,pathological hypertrophy has been associated with upregulation offetal genes including ANP, BNP, α-skeletal actin, atrial MLC-1, and β-MHC; and downregulation of genes normally expressed at higherlevels in the adult than in the fetal ventricle, such as α-MHC andSERCA2a (Izumo et al., 1988; Chien et al., 1991; MacLellan &Schneider, 2000). MHC is the major component of myosin, theprotein complex responsible for driving contraction in muscle cells. Inrodents, β-MHC is the predominant isoform present in the prenatalheart, but is down-regulated soon after birth when α-MHC isexpressed (Morkin, 2000). During pathological hypertrophy theincreased expression of β-MHC and fall in α-MHC may represent anadaptive response, as β-MHC is slower than α-MHC at catalyzing thehydrolysis of ATP (the chemical reaction drivingmyocyte contraction)leading to slower, more economical, contractile function (Swynghe-dauw, 1986; Izumo et al., 1987; Dorn et al., 1994; Swynghedauw,1999). Recapitulation of the fetal gene program and switch incontractile protein composition does not commonly occur in modelsof physiological hypertrophy e.g. exercise-induced hypertrophy(McMullen et al., 2003) (Fig. 4). The direct impact of changes infetal gene expression on cardiac growth, function and fibrosis remainunclear. While fetal genes are often upregulated in models ofpathological hypertrophy, this may be a compensatory response toprotect the heart. ANP and BNP signaling have antihypertrophicactions within cardiac myocytes (Woods, 2004). Furthermore, sometransgenic models of physiological hypertrophy have been associatedwith amodest upregulation of fetal genes (e.g. IGF1R (McMullen et al.,2004b) and MEK1 (Bueno et al., 2000)), whereas a model ofintermittent pressure overload was associated with a pathologicalphenotype but no upregulation of the fetal gene program (Perrino etal., 2006). Finally, some studies have demonstrated that a small/normal heart size phenotype can be associated with activation of thefetal gene program (Shioi et al., 2000; Antos et al., 2002). Thus, untilthe biological significance of changes in the fetal gene program is

better understood models of cardiac hypertrophy are probably bestdefined based on functional and structural parameters.

Transcription factors including GATA4, GATA6, Csx/Nkx2.5, MEF2,c-jun, c-fos, c-myc, nuclear factor-κB, and NFAT have been implicatedfor the activation of cardiac genes in response to hypertrophic stimuli(Sadoshima & Izumo, 1997; Aoki & Izumo, 2001; Akazawa & Komuro,2003). Of note, Gata4 has been implicated in the regulation of anumber of genes associated with pathological hypertrophy (e.g. ANP,BNP, α-skeletal actin, and β-MHC) but may also be important forphysiological growth. A recent study demonstrated that mice withreduced GATA4 had mild cardiac dysfunction and reduced heartweight under basal conditions. In response to pressure overload,GATA4 deficient mice developed eccentric hypertrophy and heartfailure associated with marked apoptosis and fibrosis (Bisping et al.,2006).

NGF1A-binding protein (Nab1) is a transcriptional repressor forearly growth response transcription factors. Nab1 appears to be aspecific regulator of pathological cardiac hypertrophy. Cardiac-specific Nab1 transgenic mice displayed a blunted hypertrophicresponse to adrenergically-induced and pressure overload-inducedhypertrophy whereas physiological growth (development or exer-cise-induced hypertrophy) was not affected (Buitrago et al., 2005).

Profiling studies are beginning to provide a more global view ofdifferences in gene expression in various hypertrophic models (seeSection 6.2).

6.1. Chromatin-modifying enzymes

Histone-dependent packaging of genomic DNA into chromatin is acentral mechanism for gene regulation. Nucleosomes (the basic unitof chromatin) interact to create a highly compact structure that limitsaccess of genomic DNA to transcription factors, thus repressing geneexpression (McKinsey et al., 2002). Chromatin-remodeling enzymeshave been implicated in the re-expression of the fetal gene program(McKinsey et al., 2002). The chromatin-modifying enzymes, HDACs,promote chromatin condensation and thus repress transcription(McKinsey et al., 2002).

HDACs have been grouped into three classes (I–III). Class IIaHDACs (4, 5, 7 and 9) which are regulated by signaling proteinsincluding PKC and CaMK have been implicated as suppressors ofpathological hypertrophy (Bush & McKinsey, 2009). HDAC5 andHDAC9 knockoutmice developed hypertrophywith increased age andshowed an exaggerated hypertrophic response to pressure overload(aortic constriction), however postnatal heart growth was unaffectedin the knockout models (Zhang et al., 2002a; Chang et al., 2004). By


contrast, class I HDACs (1 and 2) are reported to promotehypertrophy. Cardiac-specific HDAC2 transgenic mice developedcardiac hypertrophy associated with increased fetal gene expression(Trivedi et al., 2007). Class III HDACs (also known as sirtuins) are alsoreported to inhibit pathological hypertrophy, including apoptosis (seeBush & McKinsey, 2009).

6.2. Profiling studies of cardiac hypertrophy

In another approach to identify transcriptome changes associatedwith pathological and physiological cardiac hypertrophy, a number ofinvestigators have conducted comprehensive microarray gene ex-pression profiling studies in hearts from rodent models of patholog-ical and physiological cardiac hypertrophy, as well as tissue fromheart failure patients (Friddle et al., 2000; Hwang et al., 2000; Yang etal., 2000; Barrans et al., 2001; Hwang et al., 2002b; Diffee et al., 2003;McMullen et al., 2004b; Kong et al., 2005; Strom et al., 2005). Morerecent studies have used proteomic methods, such as 2-dimensionalpolyacrylamide gel electrophoresis (2-D PAGE) in conjunction withmass spectrometry to catalogue exercise-induced changes in thecardiac proteome (Boluyt et al., 2006; Burniston, 2009).

6.2.1. Gene expression profiling (microarray)Microarray technology is a powerful technique and quite often the

method of choice to study mRNA expression differences between acohort of samples, different transgenic mouse models, or tissuessubjected to different conditions. This technology has been used toidentifymolecular differences between physiological and pathologicalhypertrophy in a number of transgenic rodent models (Friddle et al.,2000; McMullen et al., 2004b; Kong et al., 2005; Strom et al., 2005), aswell as in human tissue samples of non-failing hearts versus failinghearts (Hwang et al., 2000; Yang et al., 2000). The outcomes of thesestudies have been reviewed in depth (Barrans et al., 2001; Hwang etal., 2002a; Dorn 2007). In brief, these studies have identified sharedand distinct gene cluster expression profiles of physiological andpathological hypertrophy (Fig. 10). Genes associated with patholog-ical hypertrophy were largely from inflammation, apoptotic, cardiacfetal gene, and oxidative stress clusters. On the other hand, genes thatwere associated with physiological hypertrophy were predominatelyinvolved in cell survival, fatty acid oxidation, insulin signaling,epidermal growth factor signaling and HSF1 expression (Fig. 10)(Aronow et al., 2001; McMullen et al., 2004b; Kong et al., 2005; Stromet al., 2005; Mirotsou et al., 2006). Cardiac apoptosis has been shownto be involved in various human and animal models of heart failure(Kang & Izumo, 2000), including the Gαq transgenic mouse whichdevelops hypertrophy and heart failure (Aronow et al., 2001).Expression of genes that are involved with fatty acid oxidation inphysiological models are consistent with the known increase in fattyacid oxidation in response to exercise (see Section 5.4). These studies,in addition to the data obtained from genetic mouse models, lendfurther support to the notion that distinct molecular mechanisms canregulate pathological and physiological cardiac hypertrophy. Mem-bers of the IGF1/EGF signaling pathway showed statistically signifi-cant changes in a rat model of physiological hypertrophy, incomparison to compensated pathological hypertrophy (Dahl saltsensitive rats on a high salt diet) (Kong et al., 2005). Anotherapplication of microarray technology is the discovery of new drugtargets. Identification of novel genes that play important roles inmediating physiological hypertrophy and protection may open upnew avenues for treating patients with heart failure (discussedfurther in Section 8). In general, research and therapy has concen-trated on identifying and inhibiting pathological processes. Anothertherapeutic strategy may be to activate novel regulators of physio-logical hypertrophy that have been identified from gene expressionprofiling studies (McMullen et al., 2004b; Kong et al., 2005; Lin et al.,2010).

Gene expression profiling has also been utilized to examinedifferences between pathological eccentric and concentric hypertro-phy. Rat models of concentric hypertrophy (aortic constriction forpressure overload) and eccentric hypertrophy (aortocaval shunt forvolume overload) with similar degrees of cardiac hypertrophy wereassociated with different gene expression patterns (Miyazaki et al.,2006). Sixty-four genes behaved similarly between the 2 models but93 genes were altered only in the pressure overload model and 134genes were differentially expressed in the volume overload model. Inanother study, comparisons were made between a model ofpathological hypertrophy (pressure overload by ascending aorticbanding for 1 week) and physiological hypertrophy (chronic swimtraining for 4 weeks) in mice. Only a small percentage (approximately3%) of genes were regulated in a similar manner between the 2models (Cardiogenomics, 2001–2003).

6.2.2. ProteomicsInvestigators have also used proteomic techniques to identify

changes in expression, splice variation and post translationalmodifications in models of cardiac hypertrophy (Boluyt et al., 2006;Burniston, 2009). Treadmill exercise-trained rats showed cardiachypertrophy, with a 14–18% increase in heart weight to body weightratio compared to sedentary controls (Boluyt et al., 2006). Analysis of2-dimensional electrophoresis gels revealed protein spots that weredecreased, increased, or detected exclusively in exercise trainedhearts compared to controls. Heat shock protein 20 (Hsp20)represented a protein exclusively expressed in exercise trained hearts(identified by mass spectrometry and immunoblotting). A later studycorroborated this finding in another rat model, but in a setting ofmoderate exercise that is similar to physical activity guidelines forhumans (Burniston, 2009).

Hsp20 belongs to the subfamily of small heat shock proteins inwhich there are 10 knownmembers in mammalian species (Fan et al.,2005a). Hsp20 contains three phosphorylation sites, serine 16, serine59, and serine 157, but conclusions on the role of Hsp20 have mostlybeen based on serine 16 phosphorylation (Fan et al., 2005a). Heatshock proteins have been involved in the preservation of myocardialfunction after ischemia/reperfusion (Kingma, 1999). Studies haveshown that Hsp20 enhances myocardial contraction in vitro (Chu etal., 2004), and cardiac-specific transgenic mice over-expressingHsp20 had enhanced cardiac function in the absence of pathologicalabnormalities (Fan et al., 2005c). Furthermore, following coronaryartery occlusion and reperfusion (24 h), Hsp20 transgenic heartsexhibited better cardiac functional recovery, and reduced infarct areacompared to wildtype hearts (Fan et al., 2005c). Finally, Hsp20transgenic mice displayed an attenuated hypertrophic response to β-AR agonist-induced cardiac hypertrophy, while retaining enhancedcardiac function. Transgenic expression also prevented the β-ARagonist-induced increase in fetal genes (ANP, BNP), fibrosis, andreduced apoptosis (Fan et al., 2006). In vitro experiments from thisstudy suggest that Hsp20 is able to inhibit apoptosis signal regulatingkinase 1, which in turn leads to protection from β-AR agonist-inducedcardiac hypertrophy/remodeling (Fan et al., 2006). Together, thissuggests that proteins that play unique roles in mediating exercise-induced physiological hypertrophy may be attractive targets for thetreatment of heart disease.

6.3. microRNAs — role in cardiac hypertrophy

MicroRNAs (miRNAs) are a relatively recently discovered family ofsmall, endogenous, single-stranded RNAs that are approximately 20–25 nucleotides in length. miRNAs have emerged rapidly as a majornew direction in several different fields of research. miRNAs arepartially complementary to their mRNA targets and have animportant role in the regulation of target genes by hybridizing to 3′untranslated regions of messenger transcripts to repress their


translation or regulate degradation (Bartel, 2004; Griffiths-Jones et al.,2006). An average miRNA is estimated to affect expression ofhundreds of mRNA targets, and up to 30% of human protein codinggenes may be regulated by miRNAs (Lewis et al., 2005; Rajewsky2006).

Although miRNAs were first described in 1993 by Victor Ambroseand colleagues (Lee et al., 1993), since then, 500–1000 differentmiRNAs have been identified, however, an understanding of theirdiverse biological functions remains in its infancy. It is known thatmiRNAs play a role in a number of biological processes includingdevelopment, cell proliferation, differentiation, and apoptosis(reviewed in Sassen et al., 2008; Cordes & Srivastava, 2009).Furthermore, changes in miRNA levels have been correlated withdisease processes, which has sparked numerous academic researchand commercial interest, particularly for cancer (reviewed by Sassenet al., 2008), viral diseases (Jopling et al., 2005; Lecellier et al., 2005),andmore recently kidney disease (Kato et al., 2009; Liang et al., 2009).A number of studies have demonstrated the involvement of severalmiRNAs in cardiac development (reviewed in (Thum et al., 2008a;Catalucci et al., 2009; Cordes & Srivastava, 2009)) and in cardiacpathology (van Rooij et al., 2006; Ikeda et al., 2007; Tatsuguchi et al.,2007; van Rooij & Olson, 2007; Divakaran & Mann, 2008; Thum et al.,2008b; Rao et al., 2009; Ren et al., 2009; Tang et al., 2009). Morerecently, cardiac specific over-expression of miRNA-208a was shownto cause pathological cardiac hypertrophy, as shown by thickening ofventricular walls, depressed cardiac function and increased expres-sion of β-MHC (Callis et al., 2009). In contrast, miRNA biology ofphysiological cardiac hypertrophy has received little attention.miRNA-1 and miRNA-133 were decreased in two models ofphysiological cardiac hypertrophy (exercised trained rats and cardiacspecific Akt transgenic mice), however, these miRNAs were alsodecreased in a model of pathological hypertrophy (pressure over-load), and in patients with heart disease (Care et al., 2007). Thus, it isrecognized that further studies outlining similarities and differencesbetween the regulation of miRNAs in physiological and pathologicalhypertrophy are needed (Latronico et al., 2008). To address this gap inmiRNA biology, we recently identified miRNAs that are differentiallyregulated in a setting of physiological hypertrophy and cardiacprotection versus a model of cardiac stress associated with patholog-ical growth (Lin et al., 2010). We first selected miRNAs that weredifferentially expressed in the dnPI3K and caPI3K transgenic mousemodels. We then selected those miRNAs that were differentiallyregulated in a setting of physiological hypertrophy and cardiacprotection (caPI3K model) and cardiac stress (myocardial infarctionmodel).

Silencing of miRNAs in vivo with antagomiRNAs (chemicallymodified, cholesterol-conjugated single-stranded RNA analoguescomplementary to miRNAs) is considered a powerful approach thatmay represent a new therapeutic strategy for targeting cardiacdisease. These molecules have been shown to be effective in vivo,capable of passing through cellular membranes to inhibit miRNAaction by sequestering it from its targets (Krutzfeldt et al., 2005).

7. Gender differences in cardiac hypertrophy

An area of research that has received increasing attention is that ofdifferential hypertrophic responses associated with gender (Du et al.,2006). It is recognized that women typically develop heart diseaselater than men. One feature that is considered to help explain thebetter prognosis in females than males, is the smaller degree ofcardiac hypertrophy and/or type (concentric versus eccentric) infemales in response to cardiovascular complications such as pressureoverload (demonstrated in animal and human studies) (Du et al.,2006).

Prior to adolescence, there are no significant differences in heartsize between males and females, suggesting a similar number of

cardiac myocytes at birth, as myocytes are terminally differentiated(Zak, 1974; de Simone et al., 1995; Sugden & Clerk, 1998; Luczak &Leinwand, 2009). Following puberty however, males have 15–30%larger hearts than females, suggesting a significantly larger degree ofhypertrophy in males (de Simone et al., 1995). Men also loseapproximately 1 g of cardiac mass per year following puberty,which leads to compensatory hypertrophy to maintain adequatecardiac mass. Females, however, appear to maintain their myocytenumber and size with aging (Grandi et al., 1992; Olivetti et al., 1995;Luczak & Leinwand, 2009).

7.1. Pathological hypertrophy

From animal studies there are clear differences in the degree and/or type of pathological hypertrophy in response to cardiac insultsbetween males and females (Du et al., 2006; Podesser et al., 2007)(Table 4). Male spontaneously hypertensive rats developed morecardiac hypertrophy and left ventricular dysfunction than females.Subsequent heart failure also occurred earlier in males than females(Tamura et al., 1999). Similar findings were reported in response topressure overload (aortic-banding) (Douglas et al., 1998;Weinberg etal., 1999; Skavdahl et al., 2005). Gender differences have also beenreported in humans, though the data are generally less conclusiveowing to confounding factors (e.g. treatments, lifestyle), relativelysmall sample sizes, and the limited studies in patients with purepressure overload (i.e. in the absence of coronary heart disease).Furthermore, in human studies there is the question of the bestnormalization of left ventricular mass data (body surface area, bodymass index, height2.7 etc). Animal data is tighter because leftventricular mass can be accurately assessed at autopsy (rather thanrelying on echocardiography). However, in spite of these limitations,gender differences in cardiac hypertrophy in response to similarpressure loads (in the absence of coronary heart disease) areapparent. In normotensive men and women (age matched b69),normalized left ventricular (LV) mass was higher in men than women(Levy et al., 1987; Laufer et al., 1989). In a population of pre-menopausal and post-menopausal women with mild essentialhypertension matched with men (in regard to mean arterial pressure,age and race), pre-menopausal women had smaller left ventricularmass and higher LV performance indices than men. These genderdifferences were most pronounced before menopause and tended todisappear after menopause (Garavaglia et al., 1989). Normalized LVmass was also greater in men than women with aortic stenosis(Carroll et al., 1992). In other studies, males were found to displayeccentric hypertrophy, while females displayed concentric hypertro-phy, suggesting themale heartmay decompensate quicker (Krumholzet al., 1993; Douglas et al., 1995). Data from the Framingham HeartStudy suggest that different degrees of hypertrophy in males andfemales have an impact on clinical outcomes. Women with LVhypertrophy (free of coronary heart disease) had better clinicaloutcomes than men [age-adjusted prevalence of ventricular arrhyth-mias higher in men than women (28% versus 17%), 6 year cumulativemortality higher in men than women (38% versus 22%)] (Bikkina etal., 1993). Women were also shown to have less cardiac myocyteapoptosis in normal and in failing hearts compared with males atautopsy (Guerra et al., 1999; Patten & Karas, 2006). Interestingly,however, in settings of diabetes or hypertension women have agreater risk than men to develop cardiovascular disease (Regitz-Zagrosek, 2006), though the reasons for this remain unclear.

7.2. Physiological hypertrophy

Gender differences in physiological cardiac hypertrophy have notbeen examined widely but seem to exist based on animal studies(Table 4). For example, female rats that underwent chronic swimtraining showed an increased hypertrophic response compared with

Table 4Differential hypertrophic responses to pathological and physiological stimuli in males and females.

Pathological/physiological

Model Subject Age Female Male Reference

Pathological C57BL/6 mice→Transverseaortic constriction

Mice 2 months ↑ Hypertrophy ↑↑ Hypertrophy Skavdahl et al., 2005HW/BW 31%increase

HW/BW 64%increase

Pathological Aortic banding (ascending aorticconstriction — 4 months)

Rats 6 months ↑ Hypertrophy ↑↑ Hypertrophy Douglas et al., 1998↑ Progression toheart failure↑ Chamberdilation

Pathological Ascending aortic stenosis Rats Not specified ↑ Hypertrophy ↑ Hypertrophy Weinberg et al., 1999↑ Fetal geneexpression

↑↑ Fetal geneexpression

↑ ANP ↑↑ ANP↑ β-MHC ↑↑ β-MHC↔ SERCA2a ↓ SERCA2a

↔ Contractilereserve

↓ Contractilereserve

Pathological Dahl salt-sensitive hypertensiverats

Rats 3–4 months ↑ Hypertrophy(concentric)

↑ Hypertrophy(eccentric)

Podesser et al., 2007

↑ Septal thickness ↑ LVPWPathological Spontaneously hypertensive

heart failure ratsRats 6 months, and failing hearts (18 months

— male; 24 months — female)↑ Myocyte cross-sectional area

↑↑ Myocyte cross-sectional area

Tamura et al., 1999

↔ Cardiacfunction

↓ Cardiac function↑ Progression toheart failure↑ Mortality

Physiological Voluntary cage wheel running Mice 4 months ↑↑ Hypertrophy ↑ Hypertrophy Konhilas et al., 2004.↑ Exercisecapacity

Physiological Swim training Rats 4 months ↑↑ Hypertrophy ↑ Hypertrophy Schaible, T.F. and Scheuer, J.,1979. [male animals]Schaible, T.F. and Scheuer, J.,1981. [female animals]


their male counterparts (Schaible & Scheuer, 1979, 1981; Luczak &Leinwand, 2009). Female mice have increased exercise capacity forboth voluntary wheel or treadmill running, with females runningmore on a cage wheel than males independent of the strain or age.Furthermore, female mice performed better in endurance tests,indicative of increased cardiovascular performance (Konhilas et al.,2004; Luczak & Leinwand, 2009). While cage wheel running inducessignificant cardiac hypertrophy in both genders, females displayed agreater percent increase in cardiac mass (Konhilas et al., 2004). Todate, there appears to be no supporting data in humans.

7.3. Molecular mechanisms associatedwith gender differences in cardiac physiology

Based on clinical trials in which both genders have been includedin significant numbers, it is clear that males and females responddifferently to cardiovascular drugs. For example, ACEI and β-blockersare less effective in women and show more side effects (Regitz-Zagrosek, 2006). Digitalis also causes more deaths in women (Regitz-Zagrosek, 2006). Furthermore, the prevalence of cardiac disease isdeclining in men, but not in women (Zipes et al., 2005). Thus, it is ofgreat importance to understand the molecular mechanisms respon-sible for the different hypertrophic responses in males and females.

The molecular mechanisms underlying gender dimorphism arecomplex and are still not well understood (Babiker et al., 2002;Turgeon et al., 2004; Edwards, 2005; Mendelsohn & Karas, 2005;Luczak & Leinwand, 2009). In general, pre-menopausal women tendto be protected against cardiovascular disease compared with age-matched men, but this protection is abolished following menopause.Thus, it has been suggested that estrogen has protective propertiesand activation of signaling cascades downstream of estrogen mayexplain gender-related differences in the heart (Kannel, 2002;

Mikkola & Clarkson, 2002; Wenger, 2002; Sullivan, 2003; Zipes etal., 2005; Luczak & Leinwand, 2009).

The sex steroid hormones (estrogen, progesterone and testoster-one) and their respective receptors are thought to mediate, at least inpart, gender differences in the heart (Mendelsohn & Karas, 2005; Duet al., 2006; Luczak & Leinwand, 2009). Estrogen and estrogenreceptors (ERs) have been most extensively characterized. Both menand women produce estrogen, but circulating levels of estrogen are10–20 fold lower in men (Luczak & Leinwand, 2009). Cardiacexpression of ERα is similar in both genders, whereas ERβ expressionis significantly higher in males (Mahmoodzadeh et al., 2006).Downregulation of ERs in response to ovariectomy was associatedwith adverse cardiac remodeling and cardiac enlargement in animalstudies, suggesting ERs are important for inhibition of pathologicalhypertrophy associated with aging (Xu et al., 2003). Early studies inknockout mice suggested that ERβ rather than ERαwas important forthe development of pathological hypertrophy induced by pressureoverload and cardioprotection in ischemia–reperfusion studies (Gabelet al., 2005; Pelzer et al., 2005; Skavdahl et al., 2005). However, thesefindings have been questioned and require further investigation.

Estrogen is able to initiate both 1) genomic responses throughbinding to steroid hormone nuclear receptors, which when bound toestrogen, modulate the transcriptional activity of target genes; as wellas 2) rapid membrane-initiated, estrogen-triggered signalingresponses (non-genomic) via a plasma membrane-associated formof the receptor (Fig. 11) (de Jager et al., 2001; Konhilas et al., 2004;Deroo & Korach, 2006; Du et al., 2006; Moriarty et al., 2006). Theprotective properties of estrogen on hypertrophy appear to bemediated in part by its ability to activate Akt, and inhibit GPCR, PKC,p38-MAPK, and degrade calcineurin (Fig. 11) (Simoncini et al., 2000;Konhilas et al., 2004; Du et al., 2006; Liu et al., 2006; Donaldson et al.,2009). Estrogen has also been shown to initiate anti-hypertrophic

Fig. 11. Signaling cascades involved in estrogen-mediated cardiac hypertrophic responses. Estrogen acts via the estrogen receptor which interacts with the p85 regulatory subunit ofPI3K to induce physiological hypertrophy and attenuate pathological signaling cascades. Nuclear estrogen receptors alter gene expression to regulate cardiac hypertrophicresponses. Estrogen is also able to induce ubiquitination of calcineurin, which leads to degradation of calcineurin by the proteasome. Ang II: angiotensin II, ANP: Atrial natriureticpeptide, BNP: B-type natriuretic peptide, CN: calcineurin, ER: estrogen receptor, ERK: extracellular regulated kinase, ET-1: endothelin-1, GPCR: G protein-coupled receptor, IGF1:insulin-like growth factor 1, IRS1: insulin receptor substrate 1, PI3K: phosphoinositide 3-kinase, PKC: protein kinase C, Ub: ubiquitin.


signaling, via increased ANP and BNP expression (Fig. 11) (van Eickelset al., 2001; Jankowski et al., 2005). Activation of Akt is reported tooccur through a direct, non-nuclear pathway involving the regulatorysubunit of PI3K (Fig. 11) (Simoncini et al., 2000). Finally, estrogen isalso thought to have a positive impact on energy metabolism (up-regulate lipid utilization and down regulate glucose oxidation), inpart, through interaction with PPARs and PPARα-activated γcoactivator-1 (Keller et al., 1995; Nunez et al., 1997; Ma et al., 1998;Tcherepanova et al., 2000; Kamei et al., 2003; Schreiber et al., 2003;Schreiber et al., 2004; Bourdoncle et al., 2005; Du et al., 2006).

Testosterone is also able to initiate genomic responses via nuclearandrogen receptors that modulate transcription, as well as non-genomic responses. Adult men have approximately 10 fold highercirculating testosterone levels than females but androgen receptorsare present in both male and female hearts, suggesting testosteronehas a role in both sexes (see Luczak & Leinwand, 2009). In contrast toestrogen, testosterone is reported to have pro-hypertrophic proper-ties (Ikeda et al., 2005; Du et al., 2006). Signaling cascades activated bytestosterone in the heart requires further examination (Du et al.,2006).

7.4. Gender differences in cardiachypertrophy — molecular mechanisms based on genetic mouse models

A further understanding of the different hypertrophic responses inmales and females at the molecular level has come from studies ofboth male and female genetic mouse models. In the past, studies ongenetically modified mouse models have typically focused on malesthough there have been some studies which have examined bothgenders. Cardiac-specific over-expression of the β2-adrenergic re-ceptor, TNF-α, and phospholamban was associated with greaterpathological hypertrophy in males compared to females (Kadokami etal., 2000; Dash et al., 2003; Gao et al., 2003). By contrast, cardiacspecific transgenic expression of dn-p38α leads to more hypertrophyin females than in males under basal conditions and in response topressure overload (Liu et al., 2006). Disruption of FKBP12.6 causedpathological hypertrophy in male but not in female mice (Xin et al.,2002), and loss of CD38 (regulator of calcium homeostasis) led tohypertrophy only in male mice (Takahashi et al., 2003). In contrast,

only male mice null for both α1A/C and α1B adrenergic receptors ormuscle specific (cardiac and skeletal) transgenic mice over-expres-sing myostatin showed reduced cardiac size (O'Connell et al., 2003;Reisz-Porszasz et al., 2003). Mutations of cardiac troponin T areassociated with different hypertrophic responses that are dependenton gender under basal conditions and in response to pathologicalstimuli (e.g. Ang II and isoproterenol) (Maass et al., 2004).

8. Therapeutic strategies for the treatment of heart failure

Current therapies for heart failure include drug therapy, implan-tation of devices and surgery (see Krum & Abraham, 2009 for detailedreview). Palliative care and exercise training regimes are importantnon-pharmacological approaches that can be implemented toalleviate symptoms and improve quality of life (Flynn et al., 2009;Goodlin, 2009). This section gives an overview of current drugtherapies and the signaling proteins they target, followed by newpotential therapeutic strategies that may be implemented in thefuture based on differences between physiological and pathologicalcardiac hypertrophy.

8.1. Current drug therapy

Traditionally, research and therapy has focused on identifying andinhibiting processes associated with pathological hypertrophy, cardi-ac dysfunction, and the transition to heart failure. It is not uncommonfor heart failure patients to be prescribed between two to sevenmedications alone, including medications to treat the side effects.Heart failure medications include ACEI, diuretics, β-blockers, ARBs,hydrolazine, and nitrates (McMurray & Pfeffer, 2005). Side effects caninclude coughing, fluid retention, joint pain, hypotension, fatigue,depression, renal insufficient, anemia and headaches. ACEI and ARBsare typically the first line of defence for patients with heart failure(Hunt et al., 2009). As outlined previously, Ang II signaling via GPCRsis a stimulus for pathological hypertrophy and fibrosis. ACEI and ARBsreduce blood pressure and attenuate LV remodeling by reducingsignaling via the Ang II receptors.

β-blockers are another class of drug that are used in combinationwith ACEI/ARBs to treat patients with heart failure (Hunt et al., 2009).

Table 5Mouse models which highlight the protective effects of IGF1-PI3K-Akt signaling in settings of heart disease.

Protective mechanism Mouse model Expression/activity Evidence of protective effect in settings of cardiovascular disease

↑ IGF1 signaling IGF1 transgenic (Reiss et al., 1996)Cardiac-specific

84% increase in circulating IGF1 dueto increased secretion from cardiac myocytes

Dilated cardiomyopathy– Attenuated LV remodeling and cardiac dysfunction, prevented apoptosis (Welch et al., 2002)

Diabetic cardiomyopathy– Reduced cardiac dysfunction (Kajstura et al., 2001)

Eccentric cardiac hypertrophy– Attenuated cardiomyocyte necrosis (Li et al., 1999)

Myocardial infarction– Attenuated ventricular dilation and cell death (Li et al., 1997)

IGF1R transgenic (McMullen et al., 2004b)Cardiac-specific

20-fold increase in IGF1R expressionin cardiac myocytes

Pressure overload– Blunted pathological hypertrophy and fibrosis (McMullen et al., 2004b)

Diabetic cardiomyopathy– Reduced cadiac dysfunction and fibrosisi (Huynh et al., 2010)

↑ PI3K activity caPI3K transgenic (Shioi et al., 2000)Cardiac-specific

6.5-fold increase in PI3K(p110α)activity in cardiac myocytes

Pressure overload– Prevented cardiac dysfunction, blunted pathological hypertrophy and fibrosis (McMullen et al., 2007)

Dilated cardiomyopathy– Prolonged lifespan (McMullen et al., 2007)

Pathological hypertrophy/heart failure– Prevented fibrosis and improved cardiac function in mice overexpressing PKCβ2 (Rigor et al., 2009)

dnPI3K transgenic (Shioi et al., 2000)Cardiac-specific

77% reduction in PI3K(p110α)activity in cardiac myocytes

Pressure overload– Reduced PI3K(p110α) activity exacerbated fibrosis and cardiac dysfunction, indicating that

PI3K(p110α) is important for maintaining cardiac structure and function in settings of cardiac stress(McMullen et al., 2003; McMullen et al., 2007)Dilated cardiomyopathy

– Reduced lifespan (McMullen et al., 2007)– Induced atrial fibrillation, reduced cardiac function, increased fibrosis (Pretorius et al., 2009a)

↑ Akt activity Akt-nuc (Shiraishi et al., 2004) Increased accumulation and activationof Akt in cardiac myocyte nuclei

Pressure overload– Attenuated LV remodeling and cardiac dysfunction, improved survival (Tsujita et al., 2006)

Akt1−/− (Cho et al., 2001) Loss of Akt1 mRNA and proteinexpression due to targeted disruptionof Akt1 gene (whole body)

Pressure overload– Loss of Akt1 exacerbated hypertrophy and cardiac dysfunction, indicating that Akt is

important for protecting the heart in settings of cardiac stress (DeBosch et al., 2006b)Exercise (activates

IGF1-PI3K signaling)Voluntary cage wheel running Hypertrophic cardiomyopathy

– Reversed expression of hypertrophic markers, reduced fibrosis, inhibited apoptosis(Konhilas et al., 2006)

Swim training Dilated cardiomyopathy– Prolonged lifespan (McMullen et al., 2007)

215B.C.Bernardo

etal./

Pharmacology

&Therapeutics

128(2010)

191–227


The use of β-blockers to treat heart failure patients was firstintroduced by Waagstein et al. (1975). This was subsequentlyconfirmed in later studies (Swedberg et al., 1979, 1980; Waagsteinet al., 1989). Since these discoveries, several randomized, controlledclinical trials (e.g. CIBIS-II, MERIT-HF) and smaller studies have shownthat administration of β-blockers improved survival rates and/or wasassociated with improvement in left ventricular ejection fraction(reviewed by Molenaar & Parsonage, 2005). β-blockers reducesymptoms and improve survival by reducing signal transduction viaβ-ARs (see Bristow, 2000).

As heart failure progresses, administration of diuretics is essentialfor alleviating fluid retention (Hunt et al., 2009). Despite the successof pharmacological agents that reduce pathological remodeling,mortality remains high, with approximately one third of patientswith heart failure dying within a year of diagnosis (McMurray &Pfeffer, 2005). Thus, novel therapeutic strategies are needed to furtherreduce mortality due to heart failure.

8.2. Novel therapeutic strategies for the treatment of heart failure

Current drug treatments usually delay heart failure progressionrather than regressing it. Thus, there is an urgent need for thedevelopment of therapies that have the potential to improve functionof the failing heart. Identification of themolecular distinction betweenpathological and physiological cardiac hypertrophy has provided anew avenue for tackling this problem. An alternate strategy to directlyinhibiting pathological heart growth is to activate regulators ofphysiological heart growth.

8.3. Benefits of activating physiologicalsignaling cascades in a setting of cardiac disease

Induction of physiological cardiac hypertrophy may be a potentialtherapeutic strategy for the treatment of heart failure (see Pretorius etal., 2008; Owen et al., 2009). Regular physical activity protects againstcardiovascular disease, and exercise training in stable chronic heartfailure patient groups is safe and beneficial (Scheuer et al., 1982;Jennings et al., 1986; Nelson et al., 1986; Schaible et al., 1986;Jennings, 1995; Orenstein et al., 1995; Coats, 2000; Konhilas et al.,2006). In animal studies, exercise training was shown to reversefunctional and molecular abnormalities associated with cardiacpathology (Scheuer et al., 1982; Schaible et al., 1986; Orenstein etal., 1995; McMullen et al., 2003; Konhilas et al., 2006; McMullen et al.,2007). As described in Section 3.1.1, the IGF1-PI3K(p110α)-Aktpathway is a critical mediator of exercise-induced physiologicalhypertrophy. Studies from genetic mouse models have highlightedthe beneficial effects of this pathway in settings of cardiac stress(Table 5).

Over-expression of IGF1 or IGF1R was beneficial in models ofpressure overload (McMullen et al., 2004b), dilated cardiomyopathy(Welch et al., 2002), myocardial infarction (Li et al., 1997), decom-pensated eccentric hypertrophy (Li et al., 1999), and diabeticcardiomyopathy (Kajstura et al., 2001; Huynh et al., 2010). caPI3Kmice maintain normal cardiac function and are protected fromdeveloping pathological hypertrophy and fibrosis when subjected topressure overload (McMullen et al., 2007). In contrast, dnPI3K micewith decreased cardiac PI3K(p110α) activity had depressed cardiacfunction and increased fibrosis after pressure overload (McMullen etal., 2003; McMullen et al., 2007). Further supporting evidence of aprotective role of PI3K(p110α) came from genetically crossing caPI3Kand dnPI3K mice with a transgenic mouse model of dilatedcardiomyopathy (DCM-Tg) (McMullen et al., 2007). Under basalconditions, DCM-Tg mice had ventricular dilation, impaired systolicfunction, congestive heart failure, and premature death (Buerger et al.,2006; McMullen et al., 2007). Increasing PI3K(p110α) activity inhearts of this model by crossing DCM-Tg with caPI3K transgenic mice,

delayed the onset of heart failure, and improved lifespan. Conversely,decreasing PI3K(p110α) activity dramatically accelerated the pro-gression of heart failure and lifespan was shortened (McMullen et al.,2007). In a more recent study, reduction of PI3K(p110α) activity inanother transgenic mouse model of dilated cardiomyopathy (mam-malian sterile 20-like kinase 1; (Yamamoto et al., 2003)) caused atrialfibrillation that was associatedwith heart failure and premature death(Pretorius et al., 2009a). Furthermore, PI3K(p110α) activity wasreduced in atrial appendages from patients who developed atrialfibrillation, but not patients in sinus rhythm (Pretorius et al., 2009a).Akt1 has also been shown to protect the heart in a setting of pressureoverload-induced hypertrophy. Akt1−/− displayed more hypertrophyand cardiac dysfunction in response to aortic-banding (DeBosch et al.,2006b). Finally, the PI3K-Akt pathway may also play a role inprotecting the heart against dysfunction in a setting of pressureoverload via an interaction with an intercalated disc protein, nectin-2(McMullen 2009; Satomi-Kobayashi et al., 2009). Taken together,these studies suggest that the IGF1-PI3K(p110α)-Akt1 pathwayprotects the heart against cardiac insults (summarized in Table 5).

Mechanisms via which activation of the IGF1-PI3K(p110α)-Aktcascade leads to protection against cardiac dysfunction and progres-sion to heart failure include: anti-fibrotic properties, anti-apoptoticproperties, maintenance of proteins associated with cardiac contrac-tile function (e.g. SERCA2a), and inhibition of pathological signalingcascades (see Section 8.4) (McMullen, 2008).

Other novel therapeutic approaches that are currently underinvestigation include statin therapy, vasopressin-receptor antago-nists, inhibition of oxidative stress, improved Ca2+ handling,prevention of apoptosis, and cardiac regeneration (Landmesser andDrexler, 2005).

8.4. Possible advantages of activating physiological signaling cascades

A dual action of physiological signaling was recently identified.Studies utilizing PI3K(p110α) transgenic and Akt1 knockout micedemonstrated that the PI3K(p110α)-Akt1 pathway can inhibitpathological growth in addition to promoting physiological growth.dnPI3K transgenic mice and Akt1 knockout mice showed anexaggerated hypertrophic response to pressure overload whereasIGF1R and caPI3K showed a blunted response (McMullen et al., 2004a;DeBosch et al., 2006b; McMullen et al., 2007). The PI3K(p110α)-Akt1pathways appear to inhibit pathological growth by inhibitingsignaling proteins downstream of GPCR, including ERK1/2 and PKCβ(Fig. 5) (DeBosch et al., 2006b; McMullen et al., 2007; Rigor et al.,2009).

8.5. Activating the IGF1-PI3K pathway in a clinical setting

Epidemiological studies in the general population suggest thatserum IGF1 levels in the lower normal range are associated withincreased risk of acute myocardial infarction, ischemic heart diseaseand heart failure (Juul et al., 2002; Vasan et al., 2003; Laughlin et al.,2004). This is consistent with findings from patients with growthhormone deficiency (see review (Colao, 2008)). Patients withhypopituitarism had a 2-fold higher risk of dying from cardiovasculardisease compared with healthy controls (Rosen and Bengtsson, 1990;Tomlinson et al., 2001). Furthermore, growth hormone deficiency hasbeen associated with decreased cardiac size and impairment incardiac function (Colao et al., 2002; Shulman et al., 2003; Salerno etal., 2004). In support of the suggestion that these cardiac effects aredue to growth hormone deficiency, multiple studies have reportedthat growth hormone replacement in these patients increases heartsize and preserves/improves cardiac function (see review (Shulman etal., 2003; Salerno et al., 2004; Colao, 2008)). However, of note,patients with acromegaly (growth hormone excess) develop cardiachypertrophy that has been associated with cardiac dysfunction.


Furthermore, while growth hormone and IGF1 have been consideredas potential therapeutic agents in patients with heart failure, resultshave been conflicting (see Colao et al., 2001).

While substantial evidence shows the benefits of activating theIGF1-PI3K(p110α) pathway in the heart (see Section 8.3), there arechallenges in targeting PI3K(p110α) directly because of its numerousactions in various cell types. Of particular note, PI3K(p110α) permitscancer cells to bypass normal growth-limiting controls (McMullen &Jay, 2007). Thus, it is of interest to identify downstream targetsregulated by PI3K(p110α) that may represent more specific thera-peutic targets. We have recently identified cardiac-selective miRNAsand mRNAs regulated by PI3K(p110α) (Lin et al., 2010). Modulationof these targets are likely to be better tolerated in patients thanactivating PI3K(p110α) directly.

9. Summary

The generation and characterization of transgenic and knockoutmice have allowed investigators to use a reductionist approach todelineate molecular mechanisms that are responsible for mediatingdistinct forms of heart growth. Further progress has been accom-plished by subjecting these models to pathological and physiologicalstimuli. Recognition of distinct mechanisms responsible for theinduction of pathological and physiological cardiac hypertrophy hasprovided new possibilities for drug discovery. Identification of uniqueregulators of physiological heart growthmay lead to the developmentof innovative pharmacotherapies in the clinical management of heartfailure. A better understanding of the mechanisms responsible for thedevelopment of concentric and eccentric hypertrophy, genderdifferences, and the key mechanisms responsible for the transitionfrom hypertrophy to heart failure will also be important for thedevelopment of new and improved therapeutics with an ability toimprove function of the failing heart as opposed to delaying diseaseprogression.

Acknowledgments

We acknowledge funding support from the National Health andMedical Research Council of Australia (NHMRC) and the NationalHeart Foundation of Australia. KLW and LP are supported byAustralian Postgraduate Awards and Baker IDI Foundation Postgrad-uate Awards. JRM is supported by an Australian Research CouncilFuture Fellowship and holds an Honorary NHMRC Research Fellow-ship. We also thank Nelly Cemerlang and Joon Win Tan foradministrative support.

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