1. P H Y S I C I A N S ’ A C A D E M Y F O R C A R D I O V A S C U L A R E D U C A T I O N Targeting the Renin Angiotensin System: Past, Present and Future Thomas Unger, MD Charité University Medicine Berlin Germany Slide lecture prepared and held by: Cardio Diabetes Master Class October 15-17, 2010, Dublin

2. CCR The Renin-Angiotensin-System AngiotensinogenAngiotensinogen Angiotensin I Renin Angiotensin II ACE AT 2 ANG II AT 1 ANG II ACE2 Ang-(1-9) Ang-(1-7) Ang-(1-5) NEP ACE Mas-R

3. CCR Aldosterone Angiotensin II Na + -reabsorption  Proximal Na + - reabsorption  +++ + + - P glom  Angiotensin effects on the nephron

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

5. CCR ments Frag ACE Bradykinin Renin ACE AT 1 ANG II AT 2 ANG II ANG I Angiotensinogen AT1 Receptor Blockers Renin inhibitors Aldosterone antagonists Aldosterone + ACE inhibitors ACE inhibitors Drugs inhibiting the renin-angiotensin-aldosterone system CCR

6. Proportion of patients with first event (%) 0 2 4 6 8 10 12 14 16 0 612182430364248546066 Adjusted Risk Reduction: 13.0%, p = 0.021 Time (months) Change from baseline (%) in LVH determined by electrocardiography -18 -16 -14 -12 -10 -8 -6 -4 -2 0 p < 0.0001 4.4% 10.2% 15.3% 9.0% Atenolol (n=4588) Losartan (n=4605) LIFE study: Greater regression of LVH with ARB (losartan) than with β-blocker (atenolol) Atenolol (n=4588) Losartan (n=4605) Cornell Voltage-Duration Product Sokolow-Lyon Voltage Composite of CV Death, stroke and MI Dahlöf B et al. Lancet 2002 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.

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

8. CCR Comparison of IDNT- and RENAAL-Results Primary Endpoint Relative Change vs Amlodipine-based or Control Therapy (%) - 23 % - 20 % - 16 % - 25 - 20 - 15 - 10 - 5 0 vs Amlodipine vs Control IDNTRENAAL - 30 IrbesartanLosartan 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 NNT = 15

9. CCR Angiotensin II AT1 AT2 Anti-hypertensive Anti-inflammatory Anti-atherosclerotic Anti-diabetic ARB PPRE 5’3’ Gene RA PPARs RXR L p300 ARB AT1R-Antagonism (Telmisartan) and PPAR  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 Cell membrane Nuclear membrane

10. CCR Angiotensin-Receptors  Vasoconstriction  Na + -Retention  Aldosterone-Release  Proliferation  Fibrosis  Inflammation  Anti-Proliferation  Anti-Fibrosis  Anti-Inflammation  Vasodilation (?)  (Neuro-)regeneration AT 1 ANG II AT 2 ANG II

11. CCR Endothelial Cells AT2 transfection in vivo Ang II+losartan Ang II+PD123177 Ang II control injury control injury + AT 2 transfection Stoll M et al. J Clin Invest 1995 neointima Nakajima M et al. Proc Natl Acad Sci 1995

12. CCR Anti-Proliferation Anti-Fibrosis Anti-Inflammation (Neuro-)regeneration Differentiation NO Production Vasodilation (?) AT 2 ANG II Angiotensin AT2 Receptor Physiology/Pathophysiology: Endogenous tissue-protective system ANG II C 21 Compound 21 The Key: Pharmacological Stimulation of a natural protective system

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

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