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Critical Role of RAAS in Vasculoprotection: New Science. New aspects of RAAS. ACE homologues ACE2 Soluble ACE ACE substrates Ang (1 – 7) Ang (1 – 9) N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) Amyloid β -protein Formation of Ang II by non-ACE peptidases

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Critical Role of RAAS in Vasculoprotection: New Science

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Critical Role of RAAS in Vasculoprotection: New Science


New aspects of RAAS

  • ACE homologues

    • ACE2

    • Soluble ACE

  • ACE substrates

    • Ang (1–7)

    • Ang (1–9)

    • N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP)

    • Amyloid β-protein

  • Formation of Ang II by non-ACE peptidases

  • ACE signal transduction pathway

RAAS = renin-angiotensin-aldosterone system

Fleming I. Circ Res. 2006;98:887-96.


RAAS: Current and potential targets

Angiotensinogen

Renin

ACE2

Ang I

Ang (1–9)

NEP

CAGECathepsin GChymase

ACE

ACE

ACE

ACE2

Ang II

Ang (1–7)

Ang (1–5)

AT1R

AT2R

AT3R

AT4R

AT(1–7)R

masR

Aldosterone

Adapted from: Ferrario CM, Strawn WB. Am J Cardiol. 2006;98:121-8.Duprez DA. J Hypertens. 2006;24:983-91.


Impact of ACEI on ACE signaling pathway

ACE

ACE inhibitor

NH2

Extracellular

Clinical significance of this pathway is under investigation

MKK7

Cytosol

CK2

JNK

COOH

cJun

JNK

P

P

cJun

P

cJun

P

P

cJun

cJun

P

cJun

P

cJun

Nucleus

AP-1

Gene expression(ACE, COX-2)

Fleming I et al. Physiology. 2005;20:91-5.


ACE metabolism

Actions of ACE, kininase II

Asp-Arg-Val-Tyr-lie-His-Pro-Phe-His-Leu

Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg

Angiotensin I

Bradykinin

Angiotensin II + His-Leu

Bradykinin 1–7 + Phe-Arg

Erdös EG. FASEB J. 2006;20:1034-8.


ACEI mechanism of benefit: Reduction in clinical events

Bradykinin

Angiotensin I

ACE/Kininase II

Degradation products

Angiotensin II

ACE inhibitors

Bradykinin

Angiotensin II

BP

Oxidative stress

Endothelial dysfunction

Glucose metabolism

Plaque growth

Fibrous cap stability

MMP activity

Nitric oxide

Reduction inclinical events

MMP = matrix metalloprotease

Fleming I et al. Physiology. 2005;20:91-5.


Renin inhibition prevents LVH in animal models

*

*

*

9-week-old double transgenic rats (untreated died by week 8)

LV wall thickness

Cardiac hypertrophy index

5

0.40

0.35

4

0.30

cm

mg/g

3

0.25

2

0.20

Valsartan

Aliskiren

Valsartan

Aliskiren

10

1

0.3

3

1

10

0.3

3

mg/kg/d

mg/kg/d

*P < 0.05 vs other groups †P < 0.05 vs valsartan 10 mg/kg/d

Pilz B et al. Hypertension. 2005;46:569-76.


Demonstrated benefits of AT1R blockade

Blood pressure

Heart failure symptoms

Diabetic renal disease progression

Stroke

Strauss MH, Hall AS. Circulation. 2006;114:838-54.


AT1R blockade upregulates both Ang II levels and AT2R expression

+

Both physiologic and pathologic effects have been proposed for AT2R stimulation

Ang I

Ang I

ACE

ACE

Ang II

Ang II

ARB

ARB

AT1

AT4

AT1

AT4

AT2

AT2

Vasodilation

Hypertrophy Inflammation

Strauss MH, Hall AS. Circulation. 2006;114:838-54.


Postulated role of AT2R and MMP-1 in plaque destabilization

Ang IIARB

AT1

AT2

Destabilization  Rupture  ACS

Endothelium

MMP-1

Extracellularmatrix

Intracellular inflammation

Leukocyteactivation

Vascular smooth muscle cells

Strauss MH, Hall AS. Circulation. 2006;114:838-54.


AT2R mediates cardiac myocyte enlargement during pressure overload

Agtr2–/Y AT2R-deficient mice and wild-type mice

200

160

Wild-type

*

Left ventricular mass(mg)

120

Agtr2–/Y

80

40

0

Before

2 weeks

10 weeks

Aortic-banded mice

Control (sham-operated) mice

*P < 0.05

Senbonmatsu T et al. J Clin Invest. 2000;106:R25-9.


Sustained decrease in PAI-1 antigen over time with ACEI vs ARB

N = 20 obese* patients with hypertension and insulin resistance

20

10

 PAI-1antigen(ng/mL)

0

-10

-20

1

3

4

6

Weeks

ACEI (ramipril)

ARB (losartan)

*BMI = 33.4 ramipril, 31.2 losartanP = 0.043, drug × time interaction

Brown NJ et al. Hypertension. 2002;40:859-65.


ACEIs and bradykinin oppose Ang II effects

Bradykinin

ACEI

Ang I

-

-

ACE

+

Inactive peptides

B2R

ACEI

Ang II

Vasodilation

NO

Prostaglandins

EDHF

tPA

AT1R

Vasoconstriction

Aldosterone secretion

Fibrosis

Proliferation

Oxidative stress

Matrix formation

Inflammation

Adapted from Ferrario CM, Strawn WB. Am J Cardiol. 2006;98:121-8.Adapted from Murphey L et al. Eur Heart J Suppl. 2003;5(A):A37-41.


Ang II effect in target organ damage

VSMC

Angiotensinogen

Fat cells

Renin

Aldosterone(Adrenal/CV tissues)

Angiotensin I

ACE

BP

Angiotensin II

Reduced baroreceptor sensitivity

Stroke

HF

Kidneyfailure

McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7.


Potential role of RAAS activation in metabolic syndrome and diabetes

Obesity

RAAS activation

Skeletal muscle

Pancreatic β cells

MetS

T2DM

MetS = metabolic syndrome

T2DM = type 2 diabetes

Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.Paul M et al. Physiol Rev. 2006;86:747-803.


RAAS activation in obesity

Circulating RAAS, N = 38 menopausal women

*

12

90

*

9

60

Renin(ng/l)

Aldosterone (ng/l)

6

30

3

0

0

Lean

Obese

Lean

Obese

60

0.10

*

45

ACE(U/l)

Ang II(nmol/l)

30

0.05

15

0

0.00

Lean

Obese

Lean

Obese

*P < 0.05

Engeli S et al. Hypertension. 2005;45:356-62.


RAAS activation contributes to obesity-related hypertension

Obesity

Leptin

Renal medullary compression

RAAS activation

Sodium reabsorption

Renal vasodilation

SNS activation

Volume expansion

Arterial hypertension

SNS = sympathetic nervous system

Sharma AM. Hypertension. 2004;44:12-19.


ACEIs: Potential mechanisms of improved glucose metabolism

Angiotensin I

Bradykinin

ACE/Kininase II

Degradation products

Angiotensin II

ACE inhibitors

Angiotensin II

Bradykinin

Nitric oxide

Skeletal muscleblood flow

Glucose metabolism

Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.


Role of Ang II in insulin resistance: Focus on signaling pathways

BK

NO

BK2 receptor

+

NO

Glucose transport

Akt1

+

Insulin receptor

+

+

+

GLUT-4 trans-location

Insulin

IRS-1

PI3-K

+

-

GLUT-4 biosynthesis

-

GLUT-4

AT1 receptor

Ang II

Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.


ACEIs improve glucose uptake in peripheral tissue

KK-Ay mouse model of T2DM

500

*

400

Evidence for bradykinin-mediated effect

Rate constant of 2-[3H]DG uptake

300

200

100

0

Control

Temocapril

Temocapril + HOE 140

Temocapril + L-NAME

HOE 140

L-NAME

*P < 0.05 vs control†P < 0.05 vs temocaprilHOE 140 = bradykinin B2 receptor blockerL-NAME = nitric oxide synthase inhibitor

SOLEUS

Schiuchi T et al. Hypertension. 2002;40:329-34.


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