1 / 20

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

ady
Download Presentation

Critical Role of RAAS in Vasculoprotection: New Science

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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.

More Related