mechanisms linking angiotensin ii & atherogenesis · pathophysiology: metabolic syndrome...
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Copyright 2003 CMF Learning SystemsAtherosclerosis.ppt
Mechanisms Linking Angiotensin II & Atherogenesis
Mechanisms Linking Angiotensin II & Atherogenesis
Carlos M Ferrario, MD, FAHA,FACA, FACCProfessor and Director
Hypertension and Vascular Disease CenterWake Forest University School of Medicine
Winston-Salem, North Carolina, USA
President and CEOThe Consortium for Southeastern Hypertension Control
Carlos M Ferrario, MD, FAHA,FACA, FACCProfessor and Director
Hypertension and Vascular Disease CenterWake Forest University School of Medicine
Winston-Salem, North Carolina, USA
President and CEOThe Consortium for Southeastern Hypertension Control
Jialal et al. Hypertens 2004;44:6-11.Jialal et al. Hypertens 2004;44:6-11.
Underlying Culprit: Inflammation
“…a pivotal role for inflammation in all phases of atherosclerosis from the initiation of the fatty streak
to the culmination in acute coronary syndrome (plaque rupture).”
““……a pivotal role for inflammation in all phases of a pivotal role for inflammation in all phases of atherosclerosis from the initiation of the fatty streak atherosclerosis from the initiation of the fatty streak
to the culmination in acute coronary syndrome to the culmination in acute coronary syndrome (plaque rupture).(plaque rupture).””
HypertensionHypertension
DyslipidemiaDyslipidemia
Copyright 2002, CMF Learning SystemsMetabolic Syndrome.ppt
Current ConceptsCurrent Concepts
LipoproteinsLDL-Chol.
LipoproteinsLDL-Chol.
InflammationInflammation
OxidativeStress
OxidativeStress
AtherosclerosisAtherosclerosis
Pressor HormonesAng II, NE, AVP
Pressor HormonesAng II, NE, AVP
VasoconstrictionVasoconstrictionVascular
and CardiacRemodeling
Vascular and CardiacRemodeling
HypertensionHypertension
VascularEndothelialDysfunction
VascularEndothelialDysfunction
END STAGEVASCULAR DISEASE
END STAGEVASCULAR DISEASE
Copyright 2002, CMF Learning SystemsMetabolic Syndrome.ppt
Obesity and Metabolic Syndrome.pptCopyright CMF Learning SystemsObesity and Metabolic Syndrome.pptCopyright CMF Learning Systems
Managing Global RisksManaging Global RisksManaging Global Risks
Venus Consoling LoveFrancois Boucher
Metabolic SyndromeTruncal Obesity
(waist ≥ 40 M; ≥35 F)
Insulin Resistance(fasting glucose > 110 mg/dL)
DyslipidemiaTG (150 mg/dL)HDL-C (M < 40 mg/dL; F mg/dL)Small dense LDL
Hypertension (≥ 130/85 mm Hg)HypercoagulabilityEndothelial and Vascular Dysfunction
Metabolic SyndromeTruncal Obesity
(waist ≥ 40 M; ≥35 F)
Insulin Resistance(fasting glucose > 110 mg/dL)
DyslipidemiaTG (150 mg/dL)HDL-C (M < 40 mg/dL; F mg/dL)Small dense LDL
Hypertension (≥ 130/85 mm Hg)HypercoagulabilityEndothelial and Vascular Dysfunction
Obesity and Metabolic Syndrome.pptCopyright CMF Learning SystemsObesity and Metabolic Syndrome.pptCopyright CMF Learning Systems
PATHOPHYSIOLOGY:Metabolic SyndromePATHOPHYSIOLOGY:PATHOPHYSIOLOGY:Metabolic SyndromeMetabolic SyndromeAbdominal
ObesityInsulin
Resistance
Hyper-coagulability
HypertensionDyslipidemia
Endothelial DysfunctionInflammation
ResistinResistin
Angiotensin IITNF - α
Angiotensin IITNF - α
RLP’s, FFA’sRLP’s, FFA’sILIL
AGE’sAGE’sPAI-1
GP IIb/IIaPAI-1
GP IIb/IIa
PAI-1PAI-1
PAI-1TF
PAI-1TF
ROSROSNO
ROS, CaveolinROS, Caveolin
VLDLVLDL
Adapted from R Vogel, MDAdapted from R Vogel, MD
Vascular Actions of Ang II
Vascular Actions of Ang II
• Increase in superoxide anion production;• Smooth muscle proliferation;• Decrease in EDRF• Increase monocyte adherence to endothelium• Inhibition of plasminogen activation;• Lipoxygenase production by macrophages;• increase oxidase LDL;• Increase activity of NADH/NADPH oxidase.
• Increase in superoxide anion production;• Smooth muscle proliferation;• Decrease in EDRF• Increase monocyte adherence to endothelium• Inhibition of plasminogen activation;• Lipoxygenase production by macrophages;• increase oxidase LDL;• Increase activity of NADH/NADPH oxidase.
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
Hypercholesterolemia Augments Vasoconstrictor
Responses to Ang II
Hypercholesterolemia Augments Vasoconstrictor
Responses to Ang II
0
10
20
30
40
50
60
1.0 5.0 10.0 20.0Ang II, mg/kg/min
Syst
olic
Blo
od P
ress
ure,
mm
Hg
Normocholesterolemic Hypercholesterolemic
0
10
20
30
40
50
60
1.0 5.0 10.0 20.0Ang II, mg/kg/min
Syst
olic
Blo
od P
ress
ure,
mm
Hg
Normocholesterolemic Hypercholesterolemic
Nickenig et al. Circulation 1999;100:2131-2134Nickenig et al. Circulation 1999;100:2131-2134
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
Statins Reduced Vasoconstrictor Responses to Ang II in Normotensive
Hypercholesterolemic Subjects
Statins Reduced Vasoconstrictor Responses to Ang II in Normotensive
Hypercholesterolemic Subjects
010203040506070
1.0 5.0 10.0 20.0Ang II, mg/kg/min
Syst
olic
Blo
od P
ress
ure,
mm
Hg
Statin Hypercholesterolemic
010203040506070
1.0 5.0 10.0 20.0Ang II, mg/kg/min
Syst
olic
Blo
od P
ress
ure,
mm
Hg
Statin Hypercholesterolemic
Nickenig et al. Circulation 1999;100:2131-2134Nickenig et al. Circulation 1999;100:2131-2134
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
Effect of Cholesterol and Statins on Platelet AT1
Receptor Density
Effect of Cholesterol and Statins on Platelet AT1
Receptor Density
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Bm
ax, f
mol
/mg
prot
ein
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Bm
ax, f
mol
/mg
prot
ein
NormalCholesterol
NormalCholesterol
HighCholesterol
HighCholesterol
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Bm
ax, f
mol
/mg
prot
ein
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Bm
ax, f
mol
/mg
prot
ein
HighCholesterol
HighCholesterol
StatinStatin
Nickenig et al. Circulation 1999;100:2131-2134Nickenig et al. Circulation 1999;100:2131-2134
Ang II and AtherosclerosisAng II and AtherosclerosisAngiotensin IIAngiotensin II
VasoactiveVasoactive
ProliferativeProliferative Pro-oxidativePro-oxidativePermeativePermeative
VSMC CaVSMC Ca++++
VasoconstrictionVasoconstriction
HypertensionHypertension
Proto-oncogenesProto-oncogenesc-fosc-fosc-junc-junc-mycc-myc
Growth FactorsGrowth FactorsTGF-B1TGF-B1PDGFPDGFPAI-1PAI-1bFGFbFGF
MacrophagesMacrophagesEndothelial NOEndothelial NOLipoxygenaseLipoxygenaseAng II-LDLAng II-LDL
0x-LDL0x-LDL
Vascular Vascular Permeability Permeability FactorsFactors
LDL AccumulationLDL Accumulation
Endothelial Cell DysfunctionEndothelial Cell DysfunctionVSMC ProliferationVSMC ProliferationExtracellular MatrixExtracellular Matrix
Foam Cell FormationFoam Cell Formation
ApoptosisApoptosis
Occlusive Coronary Artery AtherosclerosisOcclusive Coronary Artery Atherosclerosis
ACE mRNA
lumenlumen
VASCULAR RASVASCULAR RAS
Fukuhara et al. Hypertension. 2000;35:353-359Fukuhara et al. Hypertension. 2000;35:353-359
Copyright 2002, CMF Learning SystemsMetabolic Syndrome.ppt
Strawn & Ferrario. J Cardiovasc Pharmacol 1998; 33:341-351Strawn & Ferrario. J Cardiovasc Pharmacol 1998; 33:341-351
Ang II and AtherosclerosisAng II and Atherosclerosis
CMF Learning Systemscardioprotection.pr4
adhesion molecules
monocytes'chemoattractants
monocytes'chemoattractants
LipoproteinemiaLipoproteinemia
EC Activation-Dysfunction
EC Activation-Dysfunction
Accumulationof modified
and reassembled Lp
Hyperplasiaof modified ECM
EnhancedLp Transport
Foam CellFoam CellLp Trapping
Losartan (?)Losartan (?)
MONOCYTES ADHERENCE TO VASCULAR ENDOTHELIUM[mRen2]27 Transgenic Hypertensive Rats
MONOCYTES ADHERENCE TO VASCULAR ENDOTHELIUM[mRen2]27 Transgenic Hypertensive Rats
Strawn & Ferrario. J Cardiovasc Pharmacol 1998; 33:341-351Strawn & Ferrario. J Cardiovasc Pharmacol 1998; 33:341-351
ARB and Vascular Protection
Copyright CMF Learning Systemstginjury.prs
SD mRen20
10
20
30
40
50salinehydralazinelosartan
*
*
**mon
ocyt
es/m
m2
Number of monocytes adhered to vascular endothelium (Hautchen technique).Number of monocytes adhered to vascular endothelium (Hautchen technique).
Strawn & Ferrario. J Cardiovasc Pharmacol 1998; 33:341-351Strawn & Ferrario. J Cardiovasc Strawn & Ferrario. J Cardiovasc PharmacolPharmacol 1998; 33:3411998; 33:341--351351
Experimental AtherosclerosisCynomolgus Monkeys (Macaca Fascicularies)Experimental AtherosclerosisExperimental AtherosclerosisCynomolgus Monkeys (Macaca Cynomolgus Monkeys (Macaca FasciculariesFascicularies))
• Spontaneous atherosclerosis (Prathap, 1973);
• Diet-induced atherosclerosis bears high similarity with human lesions;
• Coronary lesions similar to humans (Stary and Manilow, 1982)
• Lesion progression from initial foam cell accumulation (Small et al., 1984)
• Carotid atherosclerosis correlates with plasma lipid concentrations (Kaplan et al., 1984)
• Plasma LDL uptake increased in aortas with diet-induced fatty streaks (Ghosh et al. 1987)
•• Spontaneous atherosclerosis (Prathap, 1973);
• Diet-induced atherosclerosis bears high similarity with human lesions;
• Coronary lesions similar to humans (Stary and Manilow, 1982)
• Lesion progression from initial foam cell accumulation (Small et al., 1984)
• Carotid atherosclerosis correlates with plasma lipid concentrations (Kaplan et al., 1984)
• Plasma LDL uptake increased in aortas with diet-induced fatty streaks (Ghosh et al. 1987)
Abdominal Thoracic Arch
•Fatty streak confined to intima•Composed of macrophage foam cells
Aorta Fatty Streak in Cynomolgus MonkeysAorta Fatty Streak in Cynomolgus Monkeys
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
Losartan and Prevention of AtherosclerosisLosartan and Prevention of Atherosclerosis
ControlControlControl
LosartanLosartanLosartanCoronary Artery IntimaCoronary Artery Intima
* p < 0.01* p < 0.01
LADLAD LCXLCX0.0000.000
0.0250.025
0.0500.050
0.0750.075
**
**
mm
2m
m2
Strawn et al. Circulation, 2000
12 14 16 18 200
3
6
9
12
15
Weeks of DietM
FI
*#*#
vehiclelosartan
19
Monocyte-Derived Macrophages from Hypercholesterolemic PatientsMonocyte-Derived Macrophages from Hypercholesterolemic Patients
0
1
2
3
4
5
Before LosartanTreatment
After LosartanTreatment
0
1
2
3
4
5
Before LosartanTreatment
After LosartanTreatment
Ox-
LDL
Cel
lula
r upt
ake
(µg/
mg
cell
prot
ein)
Ox-
LDL
Cel
lula
r upt
ake
(µg/
mg
cell
prot
ein)
Hayek et al., BBRC 273:418, 2000Hayek et al., BBRC 273:418, 2000
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt Khan et al., J Am Coll Cardiol 2001;38:1662-1667Khan et al., J Am Coll Cardiol 2001;38:1662-1667
Angiotensin II AT1 Receptor Blockade Reduces Monocyte CD11b Expression in
Patients with Coronary Artery Disease
Angiotensin II AT1 Receptor Blockade Reduces Monocyte CD11b Expression in
Patients with Coronary Artery Disease
01020304050607080
Mon
ocyt
e B
indi
ng
to C
D11
(%)
0 4 12
Weeks
Control Treated
01020304050607080
Mon
ocyt
e B
indi
ng
to C
D11
(%)
0 4 12
Weeks
Control Treated
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
EVIDENCE BASEDMEDICINE
EVIDENCE BASEDMEDICINE
Can we translate basic mechanismsof the role of Ang II
in atherogenesis to prevention of vascular disease?
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
THE LIFE TRIAL: Stroke End-Points
Comparative Adjusted Risk Reduction (%)
THE LIFE TRIAL: Stroke End-Points
Comparative Adjusted Risk Reduction (%)
Copyright 2004, CMF Learning SystemsSHE 2004.pptCopyright 2004, CMF Learning SystemsSHE 2004.ppt
Understanding Vascular Atherosclerotic Disease“STROKE: Mosaic of Interacting Factors”Understanding Vascular Atherosclerotic Disease“STROKE: Mosaic of Interacting Factors”
Hemodynamic Factors
(Blood pressure)
Circulating Factors(Glucose, Insulin, RBCs,
PAI,TXA2,Uric Acid)
Cardiac remodeling/enlargement
(LV and L atria)
Vascular remodeling(Hypertrophy, vascular lesions)
Endothelial Dysfunction
Hypercoagulatory State
AtheroscleroticPlaques
Atrial Fibrillation(emboli formation)
Thrombus Formation
Embolic Occlusion
Thrombotic Occlusion
Ischemic Stroke
Plaque fragments
Plaque rupture
HemorrhagicStroke
Vascular Hemorrhage
Hypertension and StrokesHypertension and Strokes
ICH13%ICH13%
SAH13%SAH13%
Lacunar19%
Lacunar19%
Thromboembolic6%
Thromboembolic6%
Cardioembolic14%
Cardioembolic14%
Other 3%Other 3%Unknown
32%Unknown
32%
Ischemic71%
Ischemic71%
Hemorrhagic26%
Hemorrhagic26%
8 Sacco RL, et al. Stroke. 1989;20:983-989.8 Sacco RL, et al. Stroke. 1989;20:983-989.
Stroke SubtypesStroke Subtypes
ICH13%ICH13%
SAH13%SAH13%
Lacunar19%
Lacunar19%
Thromboembolic6%
Thromboembolic6%
Cardioembolic14%
Cardioembolic14%
Other 3%Other 3%Unknown
32%Unknown
32%
Ischemic71%
Ischemic71%
Hemorrhagic26%
Hemorrhagic26%
8 Sacco RL, et al. Stroke. 1989;20:983-989.8 Sacco RL, et al. Stroke. 1989;20:983-989.
Stroke SubtypesStroke Subtypes
Thrombosis 2003.pptCopyright CMF Learning SystemsThrombosis 2003.pptCopyright CMF Learning Systems
Classification of Strokes in the LIFEClassification of Strokes in Classification of Strokes in the LIFEthe LIFE
0
50
100
150
200
250
Athero/Thrombotic Embolic Hemorrhagic
LosartanAtenolol
0
50
100
150
200
250
Athero/Thrombotic Embolic Hemorrhagic
LosartanAtenolol
p=0.001
Num
ber o
f str
okes
Thrombosis 2003.pptCopyright CMF Learning SystemsThrombosis 2003.pptCopyright CMF Learning Systems
Classification of Strokes in the LIFEClassification of Strokes in Classification of Strokes in the LIFEthe LIFE
0
50
100
150
200
250
Athero/Thrombotic Embolic Hemorrhagic
LosartanAtenolol
0
50
100
150
200
250
Athero/Thrombotic Embolic Hemorrhagic
LosartanAtenolol
p=0.001
Num
ber o
f str
okes
Thrombosis 2003.pptCopyright CMF Learning SystemsThrombosis 2003.pptCopyright CMF Learning Systems
footnote
Angiotensin II (AII) and LVHAngiotensin II (AII) and LVH
Angiotensin IIAngiotensin II
Cardiac dysfunctionCardiac dysfunction
1) ProliferationDNA synthesis ↑protein synthesis ↑
2) Gene upregulationTGF-ß1 ↑collagen type I ↑collagen type III ↑fibronectin ↑
1) ProliferationDNA synthesis ↑protein synthesis ↑
2) Gene upregulationTGF-ß1 ↑collagen type I ↑collagen type III ↑fibronectin ↑
1) HypertrophyDNA synthesis →protein synthesis ↑
2) Gene reprogrammingskeletal α-actin ↑ANF ↑ß-MHC ↑
3) Necrosis
1) HypertrophyDNA synthesis →protein synthesis ↑
2) Gene reprogrammingskeletal α-actin ↑ANF ↑ß-MHC ↑
3) Necrosis
Cardiac fibroblastCardiac fibroblast
AT1AT1
Cardiac myocyteCardiac myocyte
AT1AT1
Adapted from Kim S et al. Pharmacological Reviews. 2000;52:11–34.Adapted from Kim S et al. Pharmacological Reviews. 2000;52:11–34.
footnote
Angiotensin II (AII) and LVHAngiotensin II (AII) and LVH
Angiotensin IIAngiotensin II
Cardiac dysfunctionCardiac dysfunction
1) ProliferationDNA synthesis ↑protein synthesis ↑
2) Gene upregulationTGF-ß1 ↑collagen type I ↑collagen type III ↑fibronectin ↑
1) ProliferationDNA synthesis ↑protein synthesis ↑
2) Gene upregulationTGF-ß1 ↑collagen type I ↑collagen type III ↑fibronectin ↑
1) HypertrophyDNA synthesis →protein synthesis ↑
2) Gene reprogrammingskeletal α-actin ↑ANF ↑ß-MHC ↑
3) Necrosis
1) HypertrophyDNA synthesis →protein synthesis ↑
2) Gene reprogrammingskeletal α-actin ↑ANF ↑ß-MHC ↑
3) Necrosis
Cardiac fibroblastCardiac fibroblast
AT1AT1
Cardiac myocyteCardiac myocyte
AT1AT1
Adapted from Kim S et al. Pharmacological Reviews. 2000;52:11–34.Adapted from Kim S et al. Pharmacological Reviews. 2000;52:11–34.
6
LIFE Echo: Change in LV Mass IndexLIFE Echo: Change in LV Mass Index
-25
-20
-15
-10
-5
0
Year 1 Year 2 3 4 Year 5 LastEcho
LosartanAtenolol
-25
-20
-15
-10
-5
0
Year 1 Year 2 3 4 Year 5 LastEcho
LosartanAtenolol
Change from Baseline to Year in LIFEChange from Baseline to Year in LIFE
**
* p=0.021, adjusted for baseline LVMI and baseline & in treatment BP* p=0.021, adjusted for baseline LVMI and baseline & in treatment BP
Cha
nge
(g/m
2 )C
hang
e (g
/m2 )
Devereux et al.: Circulation 110: 1456-1462, 2004.Devereux et al.: Circulation 110: 1456-1462, 2004.6
LIFE Echo: Change in LV Mass IndexLIFE Echo: Change in LV Mass Index
-25
-20
-15
-10
-5
0
Year 1 Year 2 3 4 Year 5 LastEcho
LosartanAtenolol
-25
-20
-15
-10
-5
0
Year 1 Year 2 3 4 Year 5 LastEcho
LosartanAtenolol
Change from Baseline to Year in LIFEChange from Baseline to Year in LIFE
**
* p=0.021, adjusted for baseline LVMI and baseline & in treatment BP* p=0.021, adjusted for baseline LVMI and baseline & in treatment BP
Cha
nge
(g/m
2 )C
hang
e (g
/m2 )
Devereux et al.: Circulation 110: 1456-1462, 2004.Devereux et al.: Circulation 110: 1456-1462, 2004.
Association of Carotid Atherosclerosis with LV Mass in Employed AdultsAssociation of Carotid Atherosclerosis with LV Mass in Employed Adults
0
5
10
15
20
25
30
35
1st 2nd 3rd 4th 5th
Plaque (%
0
5
10
15
20
25
30
35
1st 2nd 3rd 4th 5th
Plaque (%
Quintile of LV MassQuintile of LV Mass
Roman et al: J Am Coll Cardiol 1995;25:83-90Roman et al: J Am Coll Cardiol 1995;25:83-90
Association of Carotid Atherosclerosis with LV Mass in Employed AdultsAssociation of Carotid Atherosclerosis with LV Mass in Employed Adults
0
5
10
15
20
25
30
35
1st 2nd 3rd 4th 5th
Plaque (%
0
5
10
15
20
25
30
35
1st 2nd 3rd 4th 5th
Plaque (%
Quintile of LV MassQuintile of LV Mass
Roman et al: J Am Coll Cardiol 1995;25:83-90Roman et al: J Am Coll Cardiol 1995;25:83-90
7
LIFE: Losartan vs. Atenolol Reduced Carotid Artery HypertrophyLIFE: Losartan vs. Atenolol Reduced Carotid Artery Hypertrophy
% C
hang
e in
intim
a-m
edia
lcr
oss-
sect
iona
l are
a%
Cha
nge
in in
tima-
med
ial
cros
s-se
ctio
nal a
rea
Intima-medial thickness—change from baseline at year 3Intima-medial thickness—change from baseline at year 3
–7.9 %–7.9 %
–1.7 %–1.7 %
p<0.05p<0.05–9–9
–8–8
–7–7
–6–6
–5–5
–4–4
–3–3
–2–2
–1–1
00Atenolol (n=22)Atenolol (n=22)Losartan (n=23)Losartan (n=23)
Olsen ML et al Circulation 106(19): II-574, 2002Olsen ML et al Circulation 106(19): II-574, 20027
LIFE: Losartan vs. Atenolol Reduced Carotid Artery HypertrophyLIFE: Losartan vs. Atenolol Reduced Carotid Artery Hypertrophy
% C
hang
e in
intim
a-m
edia
lcr
oss-
sect
iona
l are
a%
Cha
nge
in in
tima-
med
ial
cros
s-se
ctio
nal a
rea
Intima-medial thickness—change from baseline at year 3Intima-medial thickness—change from baseline at year 3
–7.9 %–7.9 %
–1.7 %–1.7 %
p<0.05p<0.05–9–9
–8–8
–7–7
–6–6
–5–5
–4–4
–3–3
–2–2
–1–1
00Atenolol (n=22)Atenolol (n=22)Losartan (n=23)Losartan (n=23)
Olsen ML et al Circulation 106(19): II-574, 2002Olsen ML et al Circulation 106(19): II-574, 2002
LOSARTAN AND CARDIOVASCULAR REMODELINGLOSARTAN AND CARDIOVASCULAR REMODELING
Copyright 2000, CMF Learning SystemsLife Thrombosis 2003.ppt
ThrombosisThrombosis
MSD.pptMSD.ppt
Platelets in HypertensionPlatelets in Hypertension
3. Functional Changes
Increased aggregabilityIncrease adhesiveness
Increased spontaneous aggregation
3. Functional Changes
Increased aggregabilityIncrease adhesiveness
Increased spontaneous aggregation
1. Morphological Changes
Increased volumeChange in shapeReduced life span
1. Morphological Changes
Increased volumeChange in shapeReduced life span
2. Biochemical Changes
Elevated free Ca++Increased sensitivity to
catecholaminesHigher density of α2
adrenoreceptorsDecreased content of
catecholamines and serotoninReduced uptake of catecholamines
Reduced nitric oxide
2. Biochemical Changes
Elevated free Ca++Increased sensitivity to
catecholaminesHigher density of α2
adrenoreceptorsDecreased content of
catecholamines and serotoninReduced uptake of catecholamines
Reduced nitric oxide
Ferrario, CM 2002
CMFThromboxane.pptCopyright CMF Learning SystemsCMFThromboxane.pptCopyright CMF Learning Systems
Losartan but not Candesartan Losartan but not Candesartan Interacts with the Platelet Interacts with the Platelet TxATxA22 receptorreceptor
0
25
50
75
*
**
**
0.1 1 100
25
50
75
U46619 (µM)
% A
ggre
gatio
n
0
25
50
75
*
**
**
0.1 1 100
25
50
75
U46619 (µM)
% A
ggre
gatio
n ControlControlLosartanLosartan
CandesartanCandesartan
Li et al. J Pharmacol Exp Ther 1997; 281(3):1065-1070.Li et al J Cardiovasc Pharmacol 1998; 32(2):198-205.
Li et al J Pharmacol Exp Ther 2000; 292(1):238-246.
Li et al. J Pharmacol Exp Ther 1997; 281(3):1065-1070.LiLi et al J Cardiovasc et al J Cardiovasc PharmacolPharmacol 1998; 32(2):1981998; 32(2):198--205.205.
LiLi et al J et al J PharmacolPharmacol ExpExp TherTher 2000; 292(1):2382000; 292(1):238--246.246.CMFThromboxane.pptCopyright CMF Learning SystemsCMFThromboxane.pptCopyright CMF Learning Systems
Losartan but not Candesartan Losartan but not Candesartan Interacts with the Platelet Interacts with the Platelet TxATxA22 receptorreceptor
0
25
50
75
*
**
**
0.1 1 100
25
50
75
U46619 (µM)
% A
ggre
gatio
n
0
25
50
75
*
**
**
0.1 1 100
25
50
75
U46619 (µM)
% A
ggre
gatio
n ControlControlLosartanLosartan
CandesartanCandesartan
Li et al. J Pharmacol Exp Ther 1997; 281(3):1065-1070.Li et al J Cardiovasc Pharmacol 1998; 32(2):198-205.
Li et al J Pharmacol Exp Ther 2000; 292(1):238-246.
Li et al. J Pharmacol Exp Ther 1997; 281(3):1065-1070.LiLi et al J Cardiovasc et al J Cardiovasc PharmacolPharmacol 1998; 32(2):1981998; 32(2):198--205.205.
LiLi et al J et al J PharmacolPharmacol ExpExp TherTher 2000; 292(1):2382000; 292(1):238--246.246.
Thrombosis 2003.pptCopyright CMF Learning SystemsThrombosis 2003.pptCopyright CMF Learning Systems
Changes in TRA-EC50 ExtentChanges in TRAChanges in TRA--ECEC50 Extent50 Extent
Placebo Losartan-20
-10
0
10
20
30
40Pe
rcen
t Cha
nge
Placebo Losartan-20
-10
0
10
20
30
40Pe
rcen
t Cha
nge
Perc
ent C
hang
ePe
rcen
t Cha
nge
P < 0.001P < 0.001
Levy et al. Am J of Cardiology, 2000
Thrombosis 2003.pptCopyright CMF Learning SystemsThrombosis 2003.pptCopyright CMF Learning Systems
LosartanLosartanEXP-3174
P-450PathwayP-450
Pathway
Novel Metabolite Inhibits TxA2 and COX-2Novel Metabolite Inhibits Novel Metabolite Inhibits TxATxA22 and COXand COX--22
EXP-3179
Ferrario, 2003Ferrario, 2003
Thrombosis 2003.pptCopyright CMF Learning SystemsThrombosis 2003.pptCopyright CMF Learning Systems
Effect of EXP3179 on Platelet Aggregation and COX-2Effect of EXP3179 on Platelet Effect of EXP3179 on Platelet Aggregation and COXAggregation and COX--22
Krämer et al. Circulation Res 2002;90:770-776Krämer et al. Circulation Res 2002;90:770-776
Losartan Inhibits Platelet Aggregation in Man (via EXP-3179?)Losartan Inhibits Platelet Aggregation in Man (via EXP-3179?)
P < 0.001
TxA2-induced Platelet AggregationTxA2-induced Platelet Aggregation
0%0%10%10%20%20%30%30%40%40%50%50%60%60%70%70%80%80%90%90%
100%100%
Pre-treatment 6-hr post-treatment
PlaceboLosartan
Thrombosis 2003.pptCopyright CMF Learning SystemsThrombosis 2003.pptCopyright CMF Learning Systems
Differential Actions Blockade of TxA2 ReceptorsDifferential Actions Differential Actions Blockade of TxABlockade of TxA22 ReceptorsReceptors
ControlControl CandesartanCandesartan ValsartanValsartan LosartanLosartan EXP-3174EXP-3174 IrbesartanEXP-31790
25
50
75
100
EC50
, nM
Ferrario, CM. Current Medical Research and Opinions 20, 1797-1804, 2004.Ferrario, CM. Current Medical Research and Opinions 20, 1797-1804, 2004.
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
The Origin of AtherosclerosisThe Origin of Atherosclerosis
British Journal of Haematology, 126, 120–126, 2004British Journal of Haematology, 126, 120–126, 2004
MonocytesBone Marrow Origin
MonocytesBone Marrow Origin
Monocytes leave the blood streamto become macrophages engulfing
antigens, debrids, and lipids
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
Is the BONE MARROW the SOURCE of Atherogenesis?Is the BONE MARROW the
SOURCE of Atherogenesis?
LDLLDLLDL
LDLLDLLDLEndotheliumEndotheliumEndothelium
Vessel LumenVessel Lumen
IntimaIntima
MonocyteMonocyteMonocyte
Modified LDLModified LDLModified LDL
Bone marrow RASpromotes
differentiation ofmonocytes intoMacrophages
Bone marrow RASBone marrow RASpromotespromotes
differentiation ofdifferentiation ofmonocytes intomonocytes intoMacrophagesMacrophages
MCP-1MCPMCP--11
MacrophageMacrophageMacrophage
Ang IIAng II
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
STEPS TO EVALUATING THE HYPOTHESIS
STEPS TO EVALUATING THE HYPOTHESIS
1. Does Ang II modulate hematopoiesis?2. Is it a function of a local RAS?
3. Do dyslipidemia affect the bone marrow RAS?
1. Does Ang II modulate hematopoiesis?2. Is it a function of a local RAS?
3. Do dyslipidemia affect the bone marrow RAS?
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
HematopoieticLineage
HematopoieticLineage
Stroma Osteoclasts
Stroma Osteoclasts
Ang II Immuno Reactive ProductsRat Bone Marrow
Ang II Immuno Reactive ProductsRat Bone Marrow
Copyright 2002, CMF Learning SystemsMetabolic Syndrome.ppt
Expression of RAS ComponentsRAT BONE MARROW
Expression of RAS ComponentsRAT BONE MARROW
0
10
20
30
40
50
% c
ells
exh
ibiti
ng A
ng
II bi
ndin
g
AT1-R AT2-R0
10
20
30
40
50
% c
ells
exh
ibiti
ng A
ng
II bi
ndin
g
AT1-R AT2-R
Strawn et al. British Journal of Haematology, 126, 120–126, 2004Strawn et al. British Journal of Haematology, 126, 120–126, 2004
Copyright 2000, CMF Learning SystemsStrategies for Atherosclerosis.ppt
BONE MARROW –PRIMATES-CD34+ Progenitor Cells Express AT1 Receptors
BONE MARROW –PRIMATES-CD34+ Progenitor Cells Express AT1 Receptors
CD34+ Cell AT1 Receptor Immunodetection on CD34+ Cell
Acetylated LDL Increases Angiotensin II Binding toCD34+-Derived Myeloid Precursors
Acetylated LDL Increases Angiotensin II Binding toCD34+-Derived Myeloid Precursors
LPDHS n-LDL Ac-LDL0
25
50
75
fmol
/mg
prot
ein *
* p < 0.05
Ang
II b
indi
ng
Strawn et al., Arterio Thromb Vasc Biol 2003; 23:a-56-57Strawn et al., Arterio Thromb Vasc Biol 2003; 23:a-56-57
72 h incubation with 1.0 mg/mL Ac-LDL,Sudan IV, 400X72 h incubation with 1.0 mg/mL Ac-LDL,Sudan IV, 400X
0 12
*
Weeks of Cholesterol feeding
0
100
200
300
400
Plas
ma
Tota
l Cho
lest
erol
,m
g/dL
Induction of Hypercholesterolemia Increases Bone Marrow
Hematopoietic Precursor Cell Proliferation
Induction of Hypercholesterolemia Increases Bone Marrow
Hematopoietic Precursor Cell Proliferation
Strawn, Richmond & Ferrario, 2005Strawn, Richmond & Ferrario, 2005
0 120
25
50
75
Weeks of Cholesterol FeedingC
FU-C
/wel
l *
*p < 0.05
Immunodetectable Ang II and AT1 Receptor ExpressionIncreased by Cholesterol Feeding in
Cynomolgus Monkey Bone Marrow Cells
Immunodetectable Ang II and AT1 Receptor ExpressionIncreased by Cholesterol Feeding in
Cynomolgus Monkey Bone Marrow Cells
Ang II AT1
0
10
20
30
40
50
60
70
80
90
100
**
Expr
essi
on P
erce
ntag
e
0 12Weeks ofCholesterol feeding
0 12
Strawn, Richmond & Ferrario, 2005Strawn, Richmond & Ferrario, 2005
Ang II-stimulated arachidonic acid release from HS-5 human bone marrow stromal cells
control Ang II Ang+Los PMA80
90
100
110
120
130
140
* p<0.0001 vs Control, ∞ p<0.001 vs Ang II N = 21 experiments
*
*
∞
Control @ 100%
3 H-A
rach
icdo
nic
Aci
dR
elea
se (%
of C
ontr
ol)
Richmond et al. J Renin Angiotensin Aldosterone Syst. 2004 Dec;5(4):176-82.
Copyright 2002, CMF Learning SystemsMetabolic Syndrome.ppt
SUMMARYSUMMARYHyperlipidemia alters hematopoiesis, generating activated monocytic phenotypes
The bone marrow RAS is activated by hyperlipidemia
One result of bone marrow RAS activation by hyperlipidemia is the generation of activated monocytes that participate in atherogenesis
The bone marrow RAS may be a target for diminishing end-organ pathology where inflammation is an early initiator
Hyperlipidemia alters hematopoiesis, generating activated monocytic phenotypes
The bone marrow RAS is activated by hyperlipidemia
One result of bone marrow RAS activation by hyperlipidemia is the generation of activated monocytes that participate in atherogenesis
The bone marrow RAS may be a target for diminishing end-organ pathology where inflammation is an early initiator
Copyright 2002, CMF Learning SystemsMetabolic Syndrome.ppt
AcknowledgementsAcknowledgements
William Strawn, D.V.M., Ph.D.Renee Richmond, Ph.D.
Linda Moore Peg Gallagher, Ph.D.
Ann Tallant, Ph.D.
William Strawn, D.V.M., Ph.D.Renee Richmond, Ph.D.
Linda Moore Peg Gallagher, Ph.D.
Ann Tallant, Ph.D.