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 Fleming I. Circ Res. 2006;98:887-96. RAAS = renin-angiotensin-aldosterone system

3. RAAS: Current and potential targets Angiotensinogen Ang I AT 1 RAT 2 RAT 3 RAT 4 RAT (1–7) RmasR Ang (1–9) Ang (1–7)Ang (1–5)Ang II ACE 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 CAGE Cathepsin G Chymase Aldosterone

4. Impact of ACEI on ACE signaling pathway Fleming I et al. Physiology. 2005;20:91-5. ACE NH 2 ACE inhibitor Extracellular Cytosol COOH Nucleus Gene expression (ACE, COX-2) CK2 JNK MKK7 P JNK cJun P P P P AP-1 cJun P P Clinical significance of this pathway is under investigation

5. ACE metabolism Angiotensin IBradykinin Actions of ACE, kininase II Asp-Arg-Val-Tyr-lie-His-Pro-Phe-His-LeuArg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Angiotensin II + His-LeuBradykinin 1–7 + Phe-Arg Erdös EG. FASEB J. 2006;20:1034-8.

6. 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  BP  Oxidative stress  Endothelial dysfunction  Glucose metabolism  Plaque growth  Fibrous cap stability  MMP activity Reduction in clinical events MMP = matrix metalloprotease

7. Renin inhibition prevents LVH in animal models *P < 0.05 vs other groups † P < 0.05 vs valsartan 10 mg/kg/d mg/kg/d 10 10.33 ValsartanAliskiren 1010.33 ValsartanAliskiren 9-week-old double transgenic rats (untreated died by week 8) mg/kg/d 0.40 0.20 0.25 0.30 0.35 5 Cardiac hypertrophy index LV wall thickness † 4 3 2 * * cm mg/g * Pilz B et al. Hypertension. 2005;46:569-76.

8. Demonstrated benefits of AT 1 R blockade Blood pressure Heart failure symptoms Diabetic renal disease progression Stroke Strauss MH, Hall AS. Circulation. 2006;114:838-54.

9. AT 1 R blockade upregulates both Ang II levels and AT 2 R expression Ang I Strauss MH, Hall AS. Circulation. 2006;114:838-54. Ang II AT 2 ACE ARB AT 1 AT 4 Ang I Ang II AT 2 ACE ARB AT 1 AT 4 + Both physiologic and pathologic effects have been proposed for AT 2 R stimulation VasodilationHypertrophy Inflammation

10. Postulated role of AT 2 R and MMP-1 in plaque destabilization Strauss MH, Hall AS. Circulation. 2006;114:838-54. Destabilization  Rupture  ACS Extracellular matrix Leukocyte activation Vascular smooth muscle cells Ang II ARB AT 1 AT 2  MMP-1 Intracellular inflammation Endothelium

11. AT 2 R mediates cardiac myocyte enlargement during pressure overload Senbonmatsu T et al. J Clin Invest. 2000;106:R25-9. Agtr2 – /Y AT 2 R-deficient mice and wild-type mice Wild-type Agtr2 – /Y Before2 weeks10 weeks 0 40 80 120 160 200 Aortic-banded mice Control (sham-operated) mice Left ventricular mass (mg) * *P < 0.05

12. 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 losartan P = 0.043, drug × time interaction  PAI-1 antigen (ng/mL) 1346 Weeks 20 10 0 -10 -20 ACEI (ramipril)ARB (losartan) N = 20 obese* patients with hypertension and insulin resistance

13. ACEIs and bradykinin oppose Ang II effects Bradykinin B2RB2R Vasodilation NO Prostaglandins EDHF tPA 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 + -- AT 1 R Vasoconstriction Aldosterone secretion Fibrosis Proliferation Oxidative stress Matrix formation Inflammation

14. 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) StrokeHF Kidney failure  BP VSMC Fat cells Reduced baroreceptor sensitivity

15. 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 musclePancreatic β cells  MetS  T2DM MetS = metabolic syndrome T2DM = type 2 diabetes Obesity

16. 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) LeanObese 0 3 6 12 9 0 15 30 60 45 0 90 0.00 0.05 0.10 30 60 LeanObese LeanObeseLeanObese * * *

17. 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

18. 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 muscle blood flow  Glucose metabolism

19. Role of Ang II in insulin resistance: Focus on signaling pathways Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9. BK 2 receptor BK NO  NO Glucose transport GLUT-4 trans- location GLUT-4 biosynthesis GLUT-4 Akt1 PI3-KIRS-1 AT 1 receptor Insulin receptor Insulin + + + + + + - - Ang II

20. 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 temocapril HOE 140 = bradykinin B 2 receptor blocker L -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-[ 3 H]DG uptake ControlTemocaprilTemocapril + HOE 140 Temocapril + L -NAME HOE 140 L -NAME SOLEUS * †