signaling in the heart || || front_matter

Signaling in the Heart

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Signaling in the Heart

By

José Marín-García, M.D.Director, The Molecular Cardiology and NeuromuscularInstitute, Highland Park, NJ, USA

With contributions by

Alexander Akhmedov, Ph.D. and Vitalyi Rybin, Ph.D.Senior Research Scientist, The Molecular Cardiology and Neuromuscular Institute, Highland Park, NJ, USA

ISBN 978-1-4419-9460-8 e-ISBN 978-1-4419-9461-5DOI 10.1007/978-1-4419-9461-5Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2011928241

© Springer Science+Business Media, LLC 2011All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

José Marín-García, M.D.Director, The Molecular Cardiology and Neuromuscular InstituteRaritan Avenue 75 08904 Highland ParkNJ, [email protected]

To my wife Danièle and daughter Mélanie with love

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ART WORKS for ‘Signaling in the Heart’

Danièle M. Marin 'Signaling pathway #2' Cast Acrylic Print

Danièle M. Marin ' Signaling pathway #1' Oil painting

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The molecular phenomena of signal transduction pathways are at the core of most biological processes and are critical regulators of heart physiology and pathophysiology. These four paintings, the work of the author’s wife, Danièle M. Marin were inspired by some of these signaling pathways.

Artwork #1 Mitochondria: a receiver and integrator of signals.Artwork #2 Cell cycle signaling.Artwork #3 Rapid signaling pathways.

Artwork #4 Growth factors signaling pathways.

Danièle M. Marin 'Signaling pathway #4' Oil painting

Danièle M. Marin ‘Signaling pathway #3’ Mixed Media Painting

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Preface

Signal transduction is at the core of most biological processes and represents a critical area of research. Signal transduction is extremely important not only to molecular biology research, but also to clinical medicine in general since many diseases, such as diabetes, cardiovascular diseases, autoimmunity, and cancer, arise from defects in signal trans duction pathways.

At the present time, the complex area of cardiovascular signal transduction is in its infancy, and much of the available information came to light as a by-product of extensive research effort to understand the mechanisms of hypertrophy, apoptosis/cell death, and myocardial remodel-ing. The heart acts as both transmitter and dynamic receiver of a variety of intracellular and extracellular stimuli, as well as an integrator of numerous interacting transducers, including protein kinases and effectors, the G proteins and small G protein activators which are pro-foundly influenced by their location in the cell. Given that the targeting and localization of signaling factors and enzymes to discrete subcellular compartments or substrates are important regulatory mechanisms, ensuring specificity of signaling events in response to local stimuli, these systems deserve examination from a subcellular/organellar and a functional standpoint under both physiological and pathophysiological conditions. Moreover, cardiovascular signal-ing includes a built-in specificity, reversibility and a redundancy of its components, which while making their analysis a very complex undertaking, provides the cardiac cells with great plastic-ity to respond to insult, as well as to growth stimuli. Understanding this plasticity is fundamen-tal in the discovery of new cardiovascular signal transduction techniques and new therapies.

Gene transfer studies have shown promising results in re-engineering defective signal trans-duction pathways in animal models of cardiac dysfunction, including heart failure, as well as providing cardioprotection against insults such as myocardial ischemia. Similarly, transduc-tion engineering approaches with vascular remodeling (e.g., angiogenesis) and dysfunction (e.g., hypertension) have been successful in clinical trials. In this volume, we present what is presently known in cell signal transduction pathways, genetics, and cellular biology in heart failure, development of novel therapies for to improve cardiac function, as well as where this field is heading in the future.

As the role of genetic screening in cardiology is strengthened and as research on the mul-tiple signaling pathways involved in cardiac organogenesis and pathology progresses, the time seems appropriate for a book that comprehensively integrates known facts, what is developing and what will be known in the near future. In addition to providing a recount of past discover-ies, this book deals with areas that are of emerging interest to medical students, cardiologists, and researchers in diverse fields, eyeing new therapeutic modalities that may improve cur-rently available therapies and interventions in the management of human cardiac diseases. Furthermore, we are now witnessing the transition from the Cardiology of the past to the study of systems biology, the constructive cycle of computational model building, and the experi-mental verification capable of providing the input for exciting new discoveries and hope. The chapters in this book have been arranged in a way that the readers, who browse it, can to some degree recognize and appreciate the current thoughts and ideas on cardiovascular signaling pathways. We have tried to include original and creative scientific works as much as possible, although humbly we must say that this is a work still in progress.

x Preface

Hopefully, this book will be a valuable guide to signaling of the heart from a post-genomic perspective, and also an important introduction to new ideas and future progress.

Deciphering the mystery….progress continuesSignals are received and sent……for us to interpret

José Marín-García, M.D.Highland Park, NJ

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Contents

Part I Methodologies

1 Tools to Study Signaling .......................................................................................... 3Introduction ................................................................................................................ 3Molecular Biology Methodology ............................................................................... 3

PTMs/PPIs and Functional Proteomics ................................................................. 3Molecular Cloning ................................................................................................. 4DNA Libraries ........................................................................................................ 5Polymerase Chain Reaction ................................................................................... 6Separation of Nucleic Acids .................................................................................. 6Identification of RNA/DNA Fragments ................................................................. 7Microarrays ............................................................................................................ 7

Molecular Genetics. Genetic Engineering Techniques .............................................. 8Mutagenesis ........................................................................................................... 8Genetically Engineered Animal Models ................................................................ 8RNA Interference Methods .................................................................................... 10

Proteomics .................................................................................................................. 10Identification of Proteins/Determination of Level of Expression .......................... 11Posttranslational Modifications .............................................................................. 12Protein–Protein Interaction (Interactional Proteomics) ......................................... 13Microproteome Analysis ........................................................................................ 15

Imaging ...................................................................................................................... 15Conclusions ................................................................................................................ 16Summary .................................................................................................................... 16References .................................................................................................................. 17

Part II Normal Signaling Processes

2 Cell-Cycle Signaling, Epigenetics, and Nuclear Function .................................... 21Introduction ................................................................................................................ 21Regulators of Cell Cycle: Cyclin-Related Mechanism .............................................. 21

Phosphatases Cdc25 ............................................................................................... 23Proliferation of Embryonic Myocytes ....................................................................... 23

Nonproliferating Adult Cardiomyocytes ............................................................... 23Proliferating Vascular Cells ................................................................................... 24

Regulators of Cell Cycle: Sirtuins ............................................................................. 24Regulators of Cell Cycle: Telomerase ....................................................................... 25Regulators of Cell Cycle: Redox Signaling ............................................................... 26Regulators of Cell Cycle: MicroRNAs ...................................................................... 27Epigenetic Component of Cell Inheritance ................................................................ 27Conclusions ................................................................................................................ 28Summary .................................................................................................................... 28References .................................................................................................................. 29

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3 Signaling in the Endothelium .................................................................................. 31Introduction ................................................................................................................ 31NO Production ........................................................................................................... 31

Distribution of NO Synthases ................................................................................ 31Regulation of NOS Activity ................................................................................... 31eNOS Phosphorylation ........................................................................................... 32eNOS Nitrosylation ................................................................................................ 32eNOS and Protein–Protein Interactions ................................................................. 33

Other Endothelial Pathways ....................................................................................... 36Prostanoids (Prostaglandins and Prostacyclin) ...................................................... 36Function of Prostanoids ......................................................................................... 36

Protein Kinases .......................................................................................................... 43Conclusions ................................................................................................................ 44Summary .................................................................................................................... 44References .................................................................................................................. 45

4 Rapid Signaling Pathways ....................................................................................... 49Introduction ................................................................................................................ 49Neurohormonal Signaling .......................................................................................... 50

Biogenic Amines .................................................................................................... 50Neuropeptides ........................................................................................................ 55

Purinergic Receptors .................................................................................................. 57Peptide Hormones ...................................................................................................... 58Ca2+ as a Signaling Molecule ..................................................................................... 60Conclusions ................................................................................................................ 63Summary .................................................................................................................... 64References .................................................................................................................. 65

5 Growth Factors Signaling........................................................................................ 69Introduction ................................................................................................................ 69Protein Tyrosine Kinase Receptors ............................................................................ 69

Fibroblast Growth Factor Family ........................................................................... 70Vascular Endothelial Growth Factor ...................................................................... 70Platelet-Derived Growth Factor ............................................................................. 70Epidermal Growth Factor Family .......................................................................... 71Insulin-Like Growth Factor.................................................................................... 72Insulin .................................................................................................................... 74

Protein Serine/Threonine Kinase Receptors .............................................................. 74Transforming Growth Factor-b Superfamily ......................................................... 74

G Protein-Coupled Receptors .................................................................................... 75Urocortin ................................................................................................................ 75Adrenomedullin ..................................................................................................... 75

GFs and Development ................................................................................................ 75GFs and Myocardium Pathophysiology: Cardioprotection ....................................... 77GFs and Myocardial Pathophysiology: Cardiac Hypertrophy ................................... 78GFs and Myocardium Pathophysiology: Atherosclerosis .......................................... 78GFs and Myocardial Pathophysiology: Cardiac Fibrosis .......................................... 79GFs and Endothelium: Angiogenesis ......................................................................... 79Conclusions ................................................................................................................ 80Summary .................................................................................................................... 80References .................................................................................................................. 81

6 Ion Signaling and Electrophysiological Function ................................................. 87Introduction ................................................................................................................ 87Cardiac Action Potential ............................................................................................ 87

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General Properties of Ion Channels ........................................................................... 88Na+ Channels .............................................................................................................. 89K+ Channels ............................................................................................................... 90Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ............................. 91Cl− Channels ............................................................................................................... 93Conclusions and Future Perspectives ......................................................................... 95Summary .................................................................................................................... 95References .................................................................................................................. 96

7 Lipid Signaling Pathways in the Heart .................................................................. 99Introduction ................................................................................................................ 99Phosphoinositide Signaling in the Heart .................................................................... 99PIP

2 Signaling Associated with Dysrhythmias .......................................................... 100

Ins(1,4,5)P3 Signaling in the Heart ............................................................................ 102

Cardiac Phosphoinositide 3-Kinases and Phosphatase and Tensin Homolog ........... 103PI3K Family ........................................................................................................... 103PTEN. ..................................................................................................................... 104PI3Ka Signaling and Myocardial Hypertrophy ..................................................... 104PI3Kg Signaling: Myocardial Contractility and b-Adrenergic Signaling .............. 105

Sphingolipid Signaling in Cardiomyocytes ............................................................... 107Sphingomyelinases and Their Role in the Heart .................................................... 107Sphingosine Kinases .............................................................................................. 108Cardiac S1P Receptor Signaling ............................................................................ 110

Eicosanoid Signaling in Cardiomyocytes .................................................................. 112Phospholipases ....................................................................................................... 113Cardiac Cyclooxygenases ...................................................................................... 113Cardiac Lipoxygenases .......................................................................................... 113Cytochrome P450 Monooxygenases ...................................................................... 114

Conclusions ................................................................................................................ 114Summary .................................................................................................................... 114References .................................................................................................................. 116

Part III Mitochondria

8 Heart Mitochondria: A Receiver and Integrator of Signals ................................ 125Introduction ................................................................................................................ 125Mitochondria Signaling ............................................................................................. 125

Mitochondrial Bioenergetics .................................................................................. 126Mitochondrial Biogenesis ...................................................................................... 126

Signaling at the Mitochondria .................................................................................... 126ROS Generation and Signaling .............................................................................. 126Negative Effects of ROS ........................................................................................ 127Role of ROS in Cell Signaling ............................................................................... 129Mitochondrial K

ATP Channel .................................................................................. 129

Mitochondrial Permeability Transition Pore .......................................................... 130Mitochondrial Kinases ........................................................................................... 130Mitochondrial-related Translocations .................................................................... 131Mitochondrial Retrograde Signaling ...................................................................... 131Endoplasmic Reticulum ......................................................................................... 132

Mitochondria and Apoptosis Pathways...................................................................... 132Mitochondrial Signaling Defects and Cardiomyopathies .......................................... 135Mitochondrial Signaling in Myocardial Ischemia and Cardioprotection .................. 135Mitochondrial Signaling and Myocardial Hypertrophy ............................................. 137Key Players in Mitochondrial Signaling .................................................................... 138

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Nuclear Gene Activation ........................................................................................ 138Protein Kinases ...................................................................................................... 138Calcium Signaling .................................................................................................. 139Mitochondrial Receptors ........................................................................................ 140Signals of Survival and Stress Impact Heart Mitochondria ................................... 140Survival Signals/Apoptosis .................................................................................... 141Stress Signals ......................................................................................................... 142Metabolic Signals and UCPs ................................................................................. 142

Future Prospects: Therapeutic Targets and Directions............................................... 144Conclusions ................................................................................................................ 145Summary .................................................................................................................... 145References .................................................................................................................. 146

Part IV Pediatric Cardiology

9 Signaling Pathways in Cardiovascular Development ........................................... 155Introduction ................................................................................................................ 155Cardiac Development and Gene Expression .............................................................. 155Signaling During Cardiac Development .................................................................... 156Signaling the Cardiomyocyte During Physiological Growth..................................... 157

Cell Differentiation and Mesoderm Development ................................................. 158Cardiac Precursors Differentiation ......................................................................... 160Migration of the Cardiac Precursors ...................................................................... 162

Coordination of Signaling Pathways and Progenitor Cells Functionality in Cardiogenesis .................................................................................................. 163

Proliferation of Progenitor Cardiac Cells in Cardiac Development .......................... 164Tube Looping and Segmentation ........................................................................... 164

Other T-Box Factors ................................................................................................... 167MEF2C and HAND Proteins ..................................................................................... 167Generation of Left–Right Identity ............................................................................. 169

Proepicardium ........................................................................................................ 170Chamber Growth and Maturation .............................................................................. 171

Nuclear Regulators of Chamber Growth and Maturation ...................................... 171Chamber Septation ................................................................................................. 172Atrioventricular Junction and Formation of the Atrioventricular Cushions .......... 172Formation of the AV Valves ................................................................................... 173

Extracardiac Contribution to Normal and Abnormal Cardiac Development ............. 178Epicardium-Derived Cells ...................................................................................... 178ErbB: Integration of Extracellular Matrix Signals ................................................. 179Formation of Aortic and Pulmonic Valves ............................................................. 182

Cardiac Conduction System ....................................................................................... 183Formation of the Cardiac Conduction System ....................................................... 183Connexins and CCS ............................................................................................... 184Other Signaling Pathways and Transcriptional Regulators.................................... 184Epigenetic Factors and CCS .................................................................................. 185Endothelin-1/Neuregulin and CCS ........................................................................ 185Markers of CCS Development ............................................................................... 186Generation of the CCS ........................................................................................... 186


10 Signaling in Congenital Heart Disease ................................................................... 197Introduction ................................................................................................................ 197Etiology of CHD ........................................................................................................ 197

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Molecular Mechanisms of CHD ................................................................................ 198Alterations of Signaling Pathways Associated with Valve Abnormalities ................ 200

Noonan Syndrome ................................................................................................. 200LEOPARD Syndrome ............................................................................................ 200Costello and Cardio-Facio-Cutaneous Syndromes ................................................ 201NOTCH Signaling Pathway in CHD ..................................................................... 201

Conotruncal and Outflow Tract Defects .................................................................... 202DiGeorge Syndrome .............................................................................................. 202Williams Syndrome ................................................................................................ 202CHARGE Syndrome .............................................................................................. 202Jacobsen Syndrome ................................................................................................ 202

Cardiac Septation Abnormalities ............................................................................... 203Holt–Oram Syndrome ............................................................................................ 203Okihiro and Townes–Brocks Syndromes ............................................................... 203ErbB Signaling in CHD ......................................................................................... 204NODAL Signaling Pathway ................................................................................... 205Marfan and Marfan-Like Syndromes ..................................................................... 206

CHD-Causing Genes with Elusive Molecular Mechanism(s) ................................... 206CRELD1 Gene Mutations ...................................................................................... 206FLNA Gene Mutations ........................................................................................... 206Mutations in Other Genes ...................................................................................... 207

CHD Associated with MicroRNA Dysregulation ...................................................... 207Gene Expression Profiling in CHD ........................................................................ 207

Conclusions and Future Progress ............................................................................... 208Summary .................................................................................................................... 210References .................................................................................................................. 212

Part V Aging

11 Signaling in the Aging Heart ................................................................................... 221Introduction ................................................................................................................ 221

Animal Studies ....................................................................................................... 221Cardiac Stem and Progenitor Cells in Aging ......................................................... 222

Signaling the Endothelium in Aging.......................................................................... 223Telomeres and CV Aging ........................................................................................... 225Cellular Damage/Cell Loss, Mitochondria, and CV Aging ........................................ 228Reactive Oxidative Species Generation and CV Aging ............................................. 230Inflammation Signaling Pathways and CV Aging ..................................................... 231Neuroendocrine Signaling in CV Aging .................................................................... 232

Adrenergic and Muscarinic Receptors in the Aging Heart .................................... 232Cardiac G Protein-Coupled Receptors ................................................................... 233Thyroid Hormone/SERCA in the Aging Heart ...................................................... 234Insulin, Growth Hormone and Other Interdependent Signaling Molecules .......... 234

Pro-death and Prosurvival Signaling Pathways in Aging .......................................... 236Gene Induction in Cardiac Aging .............................................................................. 236Epigenetics and Environmental Factors in Cardiac Aging ........................................ 237Conclusions ................................................................................................................ 237Summary .................................................................................................................... 237References .................................................................................................................. 238

Part VI Signaling in Cardiovascular Disease

12 Signaling in Endomyocarditis ................................................................................. 247Introduction ................................................................................................................ 247Viral Entry into the Cardiac Myocyte ........................................................................ 247

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Innate Immunity ......................................................................................................... 248Virus-Mediated Myocardial Injury ............................................................................ 250Virus-Mediated Pathways Involved in the Development of Adaptive Immunity ...... 250Other Viruses ............................................................................................................. 252Nonviral Infective Myocarditis .................................................................................. 252Endocarditis ............................................................................................................... 253Conclusions ................................................................................................................ 253Summary .................................................................................................................... 254References .................................................................................................................. 254

13 Signaling in Hypertension ....................................................................................... 257Introduction ................................................................................................................ 257Renin–Angiotensin–Aldosteron System .................................................................... 258

Angiotensin ............................................................................................................ 258Renin.. .................................................................................................................... 259Angiotensin-Converting Enzyme ........................................................................... 260Aldosterone ............................................................................................................ 260

Sympathetic Overactivity ........................................................................................... 260Natriuretic Peptides .................................................................................................... 261RedOx Signaling ........................................................................................................ 262Mitochondrial Dysfunction ........................................................................................ 263Signaling in Dysfunctioning Endothelium................................................................. 264Conclusions ................................................................................................................ 265Summary .................................................................................................................... 266References .................................................................................................................. 267

14 Gene Expression and Signaling Pathways in Myocardial Ischemia .................... 271Introduction ................................................................................................................ 271Genetics of Myocardial Ischemia .............................................................................. 271Stress Signaling .......................................................................................................... 273Metabolic Signaling ................................................................................................... 273Myocardial Ischemia and Mitochondria Signaling .................................................... 274Ischemia and Cell Death ............................................................................................ 275Inflammatory Signaling Pathway ............................................................................... 278Other Participants’ Molecules in the Inflammatory Signaling Pathways .................. 279

Nuclear Transcription Factor Kappa B .................................................................. 279Toll-Like Receptor Signaling Pathways in Myocardial Ischemia .......................... 280Chemokines ............................................................................................................ 280

Other Signaling Pathways in Myocardial Ischemia ................................................... 281Connexin and Transforming Growth Factors Signaling ........................................ 281NO Signaling ......................................................................................................... 281


15 Signaling in Hypertrophy and Heart Failure ........................................................ 287Introduction ................................................................................................................ 287Triggers of Cardiac Hypertrophy ............................................................................... 288Promoters of the Hypertrophic Response .................................................................. 288Common Signaling Pathways in Physiological and Pathological

Cardiomyocyte Growth ................................................................................... 289Second Messengers Signaling Pathways ................................................................... 289

Adrenergic Signaling ............................................................................................. 289Muscarinic Receptors ............................................................................................. 291Cyclic GMP ........................................................................................................... 291

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Endothelin .............................................................................................................. 292Angiotensin ............................................................................................................ 292Growth Factors ....................................................................................................... 292Protease-Activated Receptors ................................................................................ 293G Proteins ............................................................................................................... 293Cyclin Signaling..................................................................................................... 294Adenylyl Cyclase ................................................................................................... 294Phospholipase C ..................................................................................................... 294Nitric Oxide ........................................................................................................... 295

Kinases and Phosphatases .......................................................................................... 295Protein Kinase A .................................................................................................... 295Protein Kinase B (PKB/Akt) and Phosphoinositide 3-Kinase ............................... 295Protein Kinase C .................................................................................................... 299Protein Kinase G .................................................................................................... 299

Ca2+-Mediated Kinase Signaling ................................................................................ 299Calcineurin/Calmodulin ......................................................................................... 299G Protein Regulated Kinases ................................................................................. 301MAP Kinases ......................................................................................................... 301

Integrating Responses: Transcription Factors and Translational Control .................. 302Role of Growth Factors .......................................................................................... 302Receptor Tyrosine Kinases..................................................................................... 302NF-kB .................................................................................................................... 303Peroxisome Proliferator-Activated Receptors a and g and Co-Factors

(RXR and PGC) .......................................................................................... 303Toll-Like Receptors ................................................................................................ 305Thyroid Hormone ................................................................................................... 305Insulin .................................................................................................................... 306

Translation Control .................................................................................................... 307Other Signaling Pathways in Hypertrophy and Heart Failure ................................... 308

Apoptosis Signaling ............................................................................................... 308Caveolae ................................................................................................................. 309Integrin Signaling ................................................................................................... 309Hypertrophic Cardiac Remodeling ........................................................................ 309

Myocardial Metabolism and Neurohormonal Signaling in Cardiac Remodeling ................................................................................... 310

Insights from Transgenic Models .......................................................................... 310Neurohormonal Changes and Cytokines ............................................................... 311

Cardiac Hypertrophy and Hypertension. Gender Differences ................................... 311Antihypertrophic Signaling Pathways ....................................................................... 312

Calcineurin Inhibitors ............................................................................................ 312Nitric Oxide/PKG I/Calcium ................................................................................. 312Diacylglycerol ........................................................................................................ 313

miRNA and Hypertrophy ........................................................................................... 313Conclusions ................................................................................................................ 313Summary .................................................................................................................... 314References .................................................................................................................. 314

16 Signaling in Diabetes and Metabolic Syndrome ................................................... 323Introduction ................................................................................................................ 323Insulin ........................................................................................................................ 323Advanced Glycation End-Products ............................................................................ 326Lipotoxicity ................................................................................................................ 327Adipocytokines .......................................................................................................... 328

Cytokines ............................................................................................................... 328Adiponectin ............................................................................................................ 329Leptin. .................................................................................................................... 331

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Ghrelin ....................................................................................................................... 332Metabolic Syndrome .................................................................................................. 332Nuclear Receptors ...................................................................................................... 333Oxidative Stress ......................................................................................................... 334Mitochondrial Dysfunction ........................................................................................ 334Genetic Basis for Diabetes and Metabolic Syndrome ............................................... 336

Genes Associated with Diabetes ............................................................................ 336Genes Involved in Metabolic Syndrome and Insulin Resistance ........................... 338


17 Dysrhythmias/Channelopathies and Signaling Pathways .................................... 351Introduction ................................................................................................................ 351Inherited Cardiac Dysrhythmias ................................................................................ 351

Long QT Syndrome ............................................................................................... 352Short QT Syndrome ............................................................................................... 355Brugada Syndrome ................................................................................................. 355Catecholaminergic Polymorphic Ventricular Tachycardia..................................... 357Familial Atrial Fibrillation ..................................................................................... 358Cardiac Conduction Defects .................................................................................. 359Sudden Death Infant Syndrome ............................................................................. 360Wolff–Parkinson–White Syndrome ....................................................................... 360

Acquired Dysrhythmias ............................................................................................. 361Dysrhythmias Associated with Defects in FAO and Mitochondrial Function ........... 362Conclusions and Future Directions ............................................................................ 363Summary .................................................................................................................... 364References .................................................................................................................. 366

18 Signaling in Atherosclerosis .................................................................................... 371Introduction ................................................................................................................ 371The Role of Lipids ..................................................................................................... 371

LDL Particles ......................................................................................................... 372HDL Particles ......................................................................................................... 372

Activation of Immune Cells in Atherosclerosis ......................................................... 374Endothelial Activation, Adhesion Molecules, and Chemokines ............................ 374Heterogeneity of Monocytes .................................................................................. 375T-Cell Activation in Vascular Inflammation .......................................................... 375Plaque Rapture ....................................................................................................... 376Macrophage Death in Atherosclerosis ................................................................... 376

Rho Kinases as Mediators of Atherosclerosis ........................................................... 377ROCKs ................................................................................................................... 377Statins. .................................................................................................................... 378ROCKs in Atherogenesis ....................................................................................... 378

Oxidative Stress ......................................................................................................... 379Nitric Oxide Is a Protector Against Atherosclerosis .............................................. 380NADPH Oxidase .................................................................................................... 381Xantine Oxidase ..................................................................................................... 382Mitochondrial Oxidative Dysfunction ................................................................... 383Antioxidant Enzymes ............................................................................................. 384

Phosphatidylinositol 3-Kinase (PI3K) Signaling ....................................................... 385TNF in Atherogenesis ................................................................................................ 385

TNF and Lipid Metabolism ................................................................................... 385TNF Effects on Endothelial Dysfunction............................................................... 386TNF and ROS Generation ...................................................................................... 387

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Antiinflammatory Factors .......................................................................................... 387TGF-b Signaling Pathway ..................................................................................... 387Peroxisome Proliferator-Activated Receptors ........................................................ 388Liver X Receptor Signaling ................................................................................... 389

Angiogenesis and Atherosclerosis ............................................................................. 390Conclusions and Future Directions ............................................................................ 390Summary .................................................................................................................... 391References .................................................................................................................. 394

Part VII Targeting Signaling in Cardiovascular Medicine

19 Stem Cells Signaling Pathways in the Heart ......................................................... 407Introduction ................................................................................................................ 407Stem Cell Types ......................................................................................................... 408

Embryonic Stem Cells ........................................................................................... 408Bone Marrow-Derived Cells .................................................................................. 409Skeletal Myoblasts ................................................................................................. 409Resident Cardiac Progenitor Cells ......................................................................... 409Induced Pluripotent Stem Cells ............................................................................. 410

Cell Delivery Techniques ........................................................................................... 410Stem Cell Signaling Pathways ................................................................................... 410

Wnt Signaling ........................................................................................................ 411Nuclear Factor-kB Signaling ................................................................................. 413SDF-1/CXCR4 Signaling....................................................................................... 415Mitogen-Activated Protein Kinases ....................................................................... 416PI3K-Akt-mTOR Signaling ................................................................................... 419

Conclusions and Future Directions ............................................................................ 421Summary .................................................................................................................... 422References .................................................................................................................. 424

20 Cardioprotection and Signaling Pathways ............................................................ 431Introduction ................................................................................................................ 431Reperfusion and Cardioprotection ............................................................................. 431Ischemic Preconditioning ........................................................................................... 432Cellular and Molecular Events in IPC ....................................................................... 433

Triggering Early IPC .............................................................................................. 433Mediators of Early IPC .......................................................................................... 434The Phosphatidylinositol 3-Kinase Pathway ......................................................... 434Protein Kinase C .................................................................................................... 434Tyrosine Kinases and MAP Kinases ...................................................................... 436IPC, ATP-Sensitive Potassium Channels and Potassium Channel Openers .......... 436

Mitochondrial Events in IPC ..................................................................................... 437Cardioprotection ........................................................................................................ 438

ROS and CP ........................................................................................................... 439Early and Late IPC Pathways..................................................................................... 439Potential Applications of CP to Clinical Medicine .................................................... 440

Mitochondrial End-Effectors of IPC Cardioprotection .......................................... 441Other Targets in IPC .................................................................................................. 443Gene Expression in Early IPC ................................................................................... 443

Second Window of Protection/Delayed Preconditioning ...................................... 443Postconditioning and Cardioprotection ...................................................................... 445Remote Conditioning ................................................................................................. 446Application in Human ................................................................................................ 447

Clinical Trials ......................................................................................................... 447Conclusions and Future Perspective .......................................................................... 448

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Summary .................................................................................................................... 449References .................................................................................................................. 449

21 Targeting Signaling Pathways ................................................................................. 455Introduction ................................................................................................................ 455Reactive Oxygen Species Generation, Effects: Antioxidant Response ..................... 456Metabolic Signaling Targets ...................................................................................... 456

PPAR Isoform-Specific Agonists ........................................................................... 457Targeting Advanced Glycation End Products ............................................................ 459Inflammation Control ................................................................................................. 459Apoptotic and Prosurvival (Proliferative) Pathways .................................................. 460b-Adrenergic Pathways and Calcium Signaling ........................................................ 461Conclusions ................................................................................................................ 462Summary .................................................................................................................... 462References .................................................................................................................. 463

Part VIII Looking to the Future

22 Signaling and the Frontiers Ahead ......................................................................... 469Introduction ................................................................................................................ 469Caveats in the Application of Targeting Specific Signaling ...................................... 469Emerging Concepts in an Integrative Approach to Cardiovascular Signaling ........... 470Current and Future Technology in Cardiovascular Signaling .................................... 470

Integrating “Omics” in Cardiomyocyte Signaling ................................................. 471Microarray and Genetic Biomarkers ...................................................................... 472Modeling Systems Approaches to Assess Signaling ............................................. 472Bioinformatics/Mathematics/Computational Biology in Signaling....................... 473

Postgenomic Contributions to New and Future Therapeutic Options in Cardiovascular Medicine ............................................................................ 474

Conclusions and Future Frontiers .............................................................................. 475Summary .................................................................................................................... 475References .................................................................................................................. 476

Glossary ............................................................................................................................ 479

Index .................................................................................................................................. 499

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