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Targeting the Renin Angiotensin System: Past, Present and Future

Cardio Diabetes Master Class October 15-17, 2010, Dublin. Targeting the Renin Angiotensin System: Past, Present and Future. Slide lecture prepared and held by:. Thomas Unger, MD Charité University Medicine Berlin Germany. Renin. Angiotensin I. Ang-(1-9). ACE2. NEP. ACE. Ang-(1-7).

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Targeting the Renin Angiotensin System: Past, Present and Future

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  1. Cardio Diabetes MasterClass October 15-17, 2010, Dublin Targeting the Renin Angiotensin System:Past, Present and Future Slide lecture prepared and held by: Thomas Unger, MD Charité University Medicine Berlin Germany

  2. Renin Angiotensin I Ang-(1-9) ACE2 NEP ACE Ang-(1-7) Angiotensin II Mas-R ACE Ang-(1-5) ANG II ANG II AT1 AT2 The Renin-Angiotensin-System Angiotensinogen

  3. Angiotensin effects on the nephron + + + + + - Angiotensin II Pglom Aldosterone Proximal Na+- reabsorption  Na+-reabsorption 

  4. Angiotensin II via AT1 RAS in cardiovascular pathology Risk factors: diabetes, obesity, smoking, age Vasoconstriction Vascular hypertrophy Endothelial dysfunction Atherosclerosis Apoptosis LVH Fibrosis Arrhythmia Heart failure MI Death Stroke Cognitive dysfunction Vascular disease Hypertension Decreased GFR Proteinuria/albuminuria Glomerulosclerosis Pro-thrombotic state Renal failure Adapted from: Chung O. & Unger T., Am J Hypertens 1999;12:150S–156S

  5. ACE inhibitors ACE inhibitors CCR Drugs inhibiting the renin-angiotensin-aldosterone system Angiotensinogen Renin inhibitors Renin Bradykinin ANG I ACE ACE Aldosterone Aldosterone antagonists + Frag ANG II ments ANG II AT1 Receptor Blockers ANG II AT2 AT1

  6. LIFE study: Greater regression of LVH with ARB (losartan) than with β-blocker (atenolol) Change from baseline (%) in LVH determined by electrocardiography Proportion of patients with first event (%) 0 16 -2 Composite of CV Death, stroke and MI 14 -4 12 4.4% -6 10 Atenolol (n=4588) -8 8 9.0% -10 10.2% 6 Losartan (n=4605) -12 p < 0.0001 4 -14 Atenolol (n=4588) Losartan (n=4605) Adjusted Risk Reduction: 13.0%, p = 0.021 2 -16 15.3% 0 -18 p < 0.0001 0 6 12 18 24 30 36 42 48 54 60 66 CornellVoltage-Duration Product Sokolow-LyonVoltage Time (months) Discontinuation as a result of all adverse events, drug-related adverse events, and serious and serious and drug-related adverse events were significantly less common in losartan patients than atenolol patients. Dahlöf B et al. Lancet 2002

  7. ANG II: Progression of Chronic Renal Disease AT1 RA Renal disease ANG II ANG II ANG II ANG II Direct Cytotoxicity Vasoconstriction Inflammation Growth Effect Angiotensinogen NF- kB TNF-a Oxidative Stress Fibroblasts Tubule Cells Profibrotic Cytokines Chemoattractants Adhesion proteins Proliferation Differentation Matrix Inflammation Fibrosis Klahr et al., 2000

  8. Comparison of IDNT- and RENAAL-Results Relative Change vs Amlodipine-based or Control Therapy (%) Primary Endpoint IDNT RENAAL 0 - 5 - 10 - 15 - 16 % - 20 - 20 % - 25 - 23 % Irbesartan Losartan - 30 vs Control vs Control vs Amlodipine NNT = 15 Lewis E.J. et al., N. Engl. J. Med. 2001; 345: 851-60 ;Brenner B.M. et al., N. Engl. J. Med. 2001; 345: 861-9

  9. AT1R-Antagonism (Telmisartan) and PPAR RA p300 L ARB ARB PPARs RXR Anti-hypertensive Anti-inflammatory Anti-atherosclerotic Anti-diabetic PPRE Gene 5’ 3’ Schupp et al Circulation 2004 Benson et al Hypertension 2004 Clasen et al Hypertension 2005 Zhao Yi et al J Neurochem 2005 Schupp et al Diabetes 2005 Schupp et al Hypertension 2006 Angiotensin II AT1 AT2 Cell membrane Nuclear membrane

  10. ANG II ANG II AT1 AT2 Angiotensin-Receptors • Vasoconstriction • Na+-Retention • Aldosterone-Release • Vasodilation (?) • (Neuro-)regeneration • Proliferation • Fibrosis • Inflammation • Anti-Proliferation • Anti-Fibrosis • Anti-Inflammation

  11. Endothelial Cells AT2 transfection in vivo control Ang II control neointima injury injury + AT2 transfection Ang II+losartan Ang II+PD123177 Nakajima M et al. Proc Natl Acad Sci 1995 Stoll M et al. J Clin Invest 1995

  12. Compound21 C 21 ANG II Angiotensin AT2 Receptor The Key: Pharmacological Stimulation of a natural protective system ANG II AT2 • • NO Production • Vasodilation (?) Physiology/Pathophysiology: Endogenous tissue-protective system • • Anti-Proliferation • • Anti-Fibrosis • • Anti-Inflammation • (Neuro-)regeneration • Differentiation

  13. Compound 21: a biased agonist ? compound 21 R*1 Cardiomyocyte diameter anti-hypertrophic and anti-inflammatory responses 120 IL6-RLA (%) 100 80 60 40 20 0 TNFa TNFa + C21 TNFa + HC control R AT2R SHP-1 ATBP

  14. (pro)renin angiotensin II- dependent effects angiotensin I RERBs 4-5 fold (renin) angiotensinogen PLZF angiotensin II- independent effects (-) RER (+) cell number (+) proliferation (-) apoptosis RER-promoter PI3K-85α-promoter end-organ damage ? The Two Sides of Renin Receptor Stimulation RER cell membrane nuclear membrane - Schefe et al Circ Res 2006 Schefe et al J Hypertension 2008

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