Cardio Diabetes Master Class October 15 17 2010
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 PHYSICIANS’ ACADEMY FOR CARDIOVASCULAR EDUCATION
The Renin-Angiotensin-System Angiotensinogen Renin Angiotensin I Ang-(1 -9) ACE 2 ACE Angiotensin II NEP Ang-(1 -7) Mas-R ACE Ang-(1 -5) ANG II AT 1 AT 2 CCR
Angiotensin effects on the nephron Angiotensin II + Pglom + + - + Aldosterone + Proximal Na+reabsorption Na+-reabsorption CCR
RAS in cardiovascular pathology Risk factors: diabetes, obesity, smoking, age Vasoconstriction Vascular hypertrophy Endothelial dysfunction Atherosclerosis Apoptosis Arrhythmia LVH Heart failure Fibrosis MI Vascular disease Hypertension Pro-thrombotic state Angiotensin II via AT 1 Stroke Death Cognitive dysfunction Decreased GFR Proteinuria/albuminuria Renal failure Glomerulosclerosis Adapted from: Chung O. & Unger T. , Am J Hypertens 1999; 12: 150 S– 156 S CCR
Drugs inhibiting the renin-angiotensin-aldosterone system Angiotensinogen Renin inhibitors Renin ACE inhibitors ACE Aldosterone antagonists AT 1 Receptor Blockers + ANG II AT 1 ANG I ACE inhibitors ACE Bradykinin ag r F ANG II m en ts ANG II AT 2 CCR
LIFE study: Greater regression of LVH with ARB (losartan) than with β-blocker (atenolol) Change from baseline (%) in LVH determined by electrocardiography 0 16 -2 14 -4 -6 12 4. 4% 10 -8 9. 0% -10 -12 -14 -16 8 6 10. 2% p < 0. 0001 Atenolol (n=4588) Losartan (n=4605) -18 4 15. 3% p < 0. 0001 Cornell Voltage-Duration Product Dahlöf B et al. Lancet 2002 Sokolow-Lyon Voltage 2 0 Proportion of patients with first event (%) Composite of CV Death, stroke and MI Atenolol (n=4588) Losartan (n=4605) Adjusted Risk Reduction: 13. 0%, p = 0. 021 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Discontinuation as a result of all adverse events, drug-related adverse events, and serious and drug-related adverse events were significantly less common CCR in losartan patients than atenolol patients.
ANG II: Progression of Chronic Renal Disease Renal disease ANG II Angiotensinogen Fibroblasts Proliferation Differentation NF- k. B Profibrotic Cytokines Matrix Fibrosis Klahr et al. , 2000 AT 1 RA TNF-a Tubule Cells ANG II Oxidative Stress Direct Cytotoxicity Vasoconstriction Inflammation Growth Effect Chemoattractants Adhesion proteins Inflammation CCR
Comparison of IDNT- and RENAAL-Results Relative Change vs Amlodipine-based or Control Therapy (%) IDNT Primary Endpoint RENAAL 0 -5 - 10 - 15 - 16 % - 20 % - 25 - 30 - 23 % Irbesartan vs Amlodipine 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 Losartan vs Control NNT = 15 vs Control CCR
AT 1 R-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 Angiotensin II ARB Cell membrane AT 1 AT 2 Nuclear membrane ARB Anti-hypertensive Anti-inflammatory Anti-atherosclerotic Anti-diabetic L PPARs p 300 PPRE 5’ RA RXR Gene 3’ CCR
Angiotensin-Receptors ANG II AT 1 AT 2 · Vasoconstriction · Na+-Retention · Aldosterone-Release · Vasodilation (? ) · (Neuro-)regeneration · Proliferation · Fibrosis · Inflammation · Anti-Proliferation · Anti-Fibrosis · Anti-Inflammation CCR
Endothelial Cells AT 2 transfection in vivo control Ang II control neointima injury Ang II+losartan Ang II+PD 123177 Stoll M et al. J Clin Invest 1995 injury + AT 2 transfection Nakajima M et al. Proc Natl Acad Sci 1995 CCR
Angiotensin AT 2 Receptor The Key: Pharmacological Stimulation of a natural protective system Physiology/Pathophysiology: Endogenous tissue-protective system C 21 II ANG Compound 21 AT 2 • NO Production • Vasodilation (? ) • • • Anti-Proliferation Anti-Fibrosis Anti-Inflammation (Neuro-)regeneration Differentiation CCR
Compound 21: a biased agonist ? R compound 21 R*1 AT 2 R Cardiomyocyte diameter SHP-1 ATBP anti-hypertrophic and anti-inflammatory responses 120 100 IL 6 -RLA (%) 80 60 40 20 0 control TNFa + C 21 TNFa + HC CCR
The Two Sides of Renin Receptor Stimulation angiotensin IIdependent effects (pro)renin angiotensin I RERBs 4 -5 fold (renin) angiotensinogen RER cell membrane PLZF nuclear membrane angiotensin IIindependent effects (-) RER - RER-promoter PI 3 K-85α-promoter Schefe et al Circ Res 2006 Schefe et al J Hypertension 2008 end-organ damage ? (+) cell number (+) proliferation (-) apoptosis CCR
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