mechanisms linking angiotensin ii & atherogenesis · pathophysiology: metabolic syndrome...

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


VascularEndothelialDysfunction

VascularEndothelialDysfunction

END STAGEVASCULAR DISEASE

END STAGEVASCULAR DISEASE

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


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



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


Ang II and AtherosclerosisAng II and AtherosclerosisAngiotensin IIAngiotensin II

VasoactiveVasoactive

ProliferativeProliferative Pro-oxidativePro-oxidativePermeativePermeative

VSMC CaVSMC Ca++++

VasoconstrictionVasoconstriction


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


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


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


EVIDENCE BASEDMEDICINE

EVIDENCE BASEDMEDICINE

Can we translate basic mechanismsof the role of Ang II

in atherogenesis to prevention of vascular disease?


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


LosartanAtenolol

p=0.001

Num

ber o

f str

okes


Classification of Strokes in the LIFEClassification of Strokes in Classification of Strokes in the LIFEthe LIFE

0

50

100

150

200

250


LosartanAtenolol

0

50

100

150

200

250


LosartanAtenolol

p=0.001

Num

ber o

f str

okes


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) HypertrophyDNA synthesis →protein synthesis ↑

2) Gene reprogrammingskeletal α-actin ↑ANF ↑ß-MHC ↑

3) Necrosis



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







3) Necrosis



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


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


LosartanAtenolol

-25

-20

-15

-10

-5

0


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.


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


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


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


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.


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


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


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?


HematopoieticLineage

HematopoieticLineage

Stroma Osteoclasts

Stroma Osteoclasts

Ang II Immuno Reactive ProductsRat Bone Marrow

Ang II Immuno Reactive ProductsRat Bone Marrow


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


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.


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


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.

mechanisms linking angiotensin ii & atherogenesis · pathophysiology: metabolic syndrome...

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