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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

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Critical Role of RAAS in Vasculoprotection: New Science

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  1. Critical Role of RAAS in Vasculoprotection: New Science

  2. 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.

  3. 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.

  4. 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.

  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.

  6. 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.

  7. 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.

  8. Demonstrated benefits of AT1R blockade Blood pressure Heart failure symptoms Diabetic renal disease progression Stroke Strauss MH, Hall AS. Circulation. 2006;114:838-54.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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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