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

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Critical Role of RAAS in Vasculoprotection: New Science

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Critical role of raas in vasculoprotection new science

Critical Role of RAAS in Vasculoprotection: New Science


New aspects of raas

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

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

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

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

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

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 at 1 r blockade

Demonstrated benefits of AT1R blockade

Blood pressure

Heart failure symptoms

Diabetic renal disease progression

Stroke

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


At 1 r blockade upregulates both ang ii levels and at 2 r expression

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 at 2 r and mmp 1 in plaque destabilization

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.


At 2 r mediates cardiac myocyte enlargement during pressure overload

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

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

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

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

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

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

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

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

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

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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