Critical Role of RAAS in Vasculoprotection: New Science.
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Transcript of Critical Role of RAAS in Vasculoprotection: New Science.
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
Fleming I. Circ Res. 2006;98:887-96.RAAS = renin-angiotensin-aldosterone system
RAAS: Current and potential targets
Angiotensinogen
Ang I
AT1R AT2R AT3R AT4R AT(1–7)R masR
Ang (1–9)
Ang (1–7) Ang (1–5)Ang II
ACE
ACEACE2
ACE2
NEP
Adapted from: Ferrario CM, Strawn WB. Am J Cardiol. 2006;98:121-8.Duprez DA. J Hypertens. 2006;24:983-91.
ACE
Renin
CAGECathepsin GChymase
Aldosterone
Impact of ACEI on ACE signaling pathway
Fleming I et al. Physiology. 2005;20:91-5.
ACE
NH2
ACE inhibitorExtracellular
CytosolCOOH
Nucleus
Gene expression(ACE, COX-2)
CK2JNK
MKK7
P JNK cJun
cJunP
cJunP
cJunPcJun
P
AP-1cJun
PcJunP
Clinical significance of this pathway is under investigation
ACE metabolism
Angiotensin I Bradykinin
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 II + His-Leu Bradykinin 1–7 + Phe-Arg
Erdös EG. FASEB J. 2006;20:1034-8.
ACEI mechanism of benefit: Reduction in clinical events
Fleming I et al. Physiology. 2005;20:91-5.
Angiotensin I
ACE/Kininase II
Degradation products
Nitric oxide
Angiotensin II
Angiotensin II
ACE inhibitors
Bradykinin
Bradykinin
BPOxidative stressEndothelial dysfunctionGlucose metabolismPlaque growthFibrous cap stabilityMMP activity
Reduction inclinical events
MMP = matrix metalloprotease
Renin inhibition prevents LVH in animal models
*P < 0.05 vs other groups †P < 0.05 vs valsartan 10 mg/kg/d
mg/kg/d101 0.3 3
Valsartan Aliskiren
101 0.3 3
Valsartan Aliskiren
9-week-old double transgenic rats (untreated died by week 8)
mg/kg/d
0.40
0.20
0.25
0.30
0.35
5Cardiac hypertrophy indexLV wall thickness
†
4
3
2
*
*
cm mg/g
*
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
Ang I
Strauss MH, Hall AS. Circulation. 2006;114:838-54.
Ang II
AT2
ACE
ARB
AT1 AT4
Ang I
Ang II
AT2
ACE
ARB
AT1 AT4
+
Both physiologic and pathologic effects have been proposed for AT2R stimulation
Vasodilation Hypertrophy Inflammation
Postulated role of AT2R and MMP-1 in plaque destabilization
Strauss MH, Hall AS. Circulation. 2006;114:838-54.
Destabilization Rupture ACS
Extracellularmatrix
Leukocyteactivation
Vascular smooth muscle cells
Ang II
ARB
AT1
AT2
MMP-1
Intracellular inflammation
Endothelium
AT2R mediates cardiac myocyte enlargement during pressure overload
Senbonmatsu T et al. J Clin Invest. 2000;106:R25-9.
Agtr2–/Y AT2R-deficient mice and wild-type mice
Wild-type
Agtr2–/Y
Before 2 weeks 10 weeks0
40
80
120
160
200
Aortic-banded miceControl (sham-operated) mice
Left ventricular
mass(mg)
*
*P < 0.05
Sustained decrease in PAI-1 antigen over time with ACEI vs ARB
Brown NJ et al. Hypertension. 2002;40:859-65.
*BMI = 33.4 ramipril, 31.2 losartanP = 0.043, drug × time interaction
PAI-1antigen(ng/mL)
1 3 4 6Weeks
20
10
0
-10
-20
ACEI (ramipril) ARB (losartan)
N = 20 obese* patients with hypertension and insulin resistance
ACEIs and bradykinin oppose Ang II effects
Bradykinin
B2R
VasodilationNOProstaglandinsEDHFtPA
Inactive peptides
Ang I
Ang II
ACE
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.
ACEI
ACEI+
- -
AT1R
VasoconstrictionAldosterone secretionFibrosisProliferationOxidative stressMatrix formationInflammation
Ang II effect in target organ damage
McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7.
Angiotensinogen
Angiotensin I
Angiotensin II
Renin
ACE
Aldosterone(Adrenal/CV tissues)
Stroke HFKidneyfailure
BP
VSMC
Fat cells
Reduced baroreceptor sensitivity
Potential role of RAAS activation in metabolic syndrome and 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
Skeletal muscle Pancreatic β cells
MetS T2DM
MetS = metabolic syndromeT2DM = type 2 diabetes
Obesity
RAAS activation in obesity
Engeli S et al. Hypertension. 2005;45:356-62.
Circulating RAAS, N = 38 menopausal women
*P < 0.05
Renin(ng/l)
ACE(U/l)
Aldosterone (ng/l)
Ang II(nmol/l)
Lean Obese0
3
6
12
9
0
15
30
60
45
0
90
0.00
0.05
0.10
30
60
Lean Obese
Lean Obese Lean Obese
* *
*
Obesity
Volume expansion
Arterial hypertension
Sharma AM. Hypertension. 2004;44:12-19.
Leptin Renal medullary compression
RAAS activation
Sodium reabsorption
Renal vasodilation SNS activation
SNS = sympathetic nervous system
RAAS activation contributes to obesity-related hypertension
ACEIs: Potential mechanisms of improved glucose metabolism
Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.
Angiotensin I
ACE/Kininase II
Degradation products
Nitric oxide
Angiotensin II
Angiotensin II
ACE inhibitors
Bradykinin
Bradykinin
Skeletal muscleblood flow
Glucose metabolism
Role of Ang II in insulin resistance: Focus on signaling pathways
Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.
BK2 receptor
BKNO
NO Glucose transport
GLUT-4 trans-
locationGLUT-4
biosynthesis
GLUT-4
Akt1
PI3-KIRS-1
AT1 receptor
Insulin receptor
Insulin
+ ++
+
+
+
-
-
Ang II
ACEIs improve glucose uptake in peripheral tissue
Schiuchi T et al. Hypertension. 2002;40:329-34.
*P < 0.05 vs control†P < 0.05 vs temocaprilHOE 140 = bradykinin B2 receptor blockerL-NAME = nitric oxide synthase inhibitor
KK-Ay mouse model of T2DM
Evidence for bradykinin-mediated effect
500
400
300
200
100
0
Rate constant of
2-[3H]DG uptake
Control Temocapril Temocapril + HOE 140
Temocapril + L-NAME
HOE 140 L-NAME
SOLEUS
*
†
