1 / 9

Vascular effects of PPAR  activation: Endothelial function

Vascular effects of PPAR  activation: Endothelial function. PPAR agonists. Improved substrate metabolism.  Thrombosis  Plaque stability.  Cell recruitment and activation .  Inflammatory response .  Vasoconstriction  Cell migration.  Foam cell formation  Cholesterol efflux.

ranit
Download Presentation

Vascular effects of PPAR  activation: Endothelial function

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. Vascular effects of PPAR activation: Endothelial function

  2. PPAR agonists Improved substrate metabolism  Thrombosis  Plaque stability  Cell recruitment and activation  Inflammatory response  Vasoconstriction  Cell migration  Foam cell formation  Cholesterol efflux  Atherogenesis Potential vascular benefits of PPAR activation Cariou B et al. Br J Diabetes Vasc Dis. 2005;5(3):126-32.

  3. Evidence on PPAR activation and favourable effects on endothelial dysfunction • PPARs involved in different dimensions of endothelial dysfunction: contractile, thrombotic, permeability and proliferative • PPAR ligands stimulate EC Nitric oxide release • PPAR agonists ameliorate EC activation via inhibition of DAG-PKC-b signalling pathway • Clinical trials in diabetic & nondiabetic patients Cariou B et al. Br J Diabetes Vasc Dis. 2005;5:126-32.

  4. PPAR activation and endothelial function Pioglitazone Pioglitazone Pioglitazone Placebo Placebo Placebo 400 600 400 P=0.01 P=0.31 P=0.07 300 300 500 Forearm Blood Flow (% Increases from baseline) 200 200 400 100 100 300 0 0 0 0.8 30 15 400 1.6 3.2 100 7.5 200 Sodium Nitroprusside (ng/min) Bradykinin (ng/min) Acetylchloline (µg/min) Campia U et al. Circulation 2006; 113: 867-75

  5. NO dependent vasodilation 100 Pioglitazone 80 +TNF (10ng/min/2h) 60 Placebo 40 MC % change Placebo +TNF (10ng/min/2h) 20 0 0 0,6 1,8 6 -20 Dosis serotonin (ng/100mlFAV/min) Endothelial dysfunction by TNF-infusion Martens FM, EurHeart J. 2006;27(13):1605-9

  6. PPAR  activation blunts progression of carotid atherosclerosis N = 173 with type 2 diabetes ns 0.08 0.04 CarotidIMT (mm) 0.00 P < 0.001 –0.04 –0.08 –0.12 P < 0.005 –0.16 0 12 24 Weeks Glimepiride 2.7 mg Pioglitazone 45 mg Langenfeld MR et al. Circulation. 2005;111:2525-31.

  7. TZDs impact carotid IMT Patients (Duration) Study (year) Treatment  IMT (mm) Minamikawa(1998) TRO 400 mgUsual care DM2 (6 mo) 0.08, TRO0.03, Usual careP < 0.001 Koshiyama(2001) PIO 30 mgUsual care DM2(6 mo) 0.08, PIO 0.02, Usual careP < 0.001 Sidhu(2004) ROSI 8 mgPlacebo Stable CAD(48 wk) 0.01, ROSI 0.03, PlaceboP = 0.03 Langenfeld(2005) PIO 45 mgGLIM 2.7 mg (mean) DM2 (6 mo) 0.05, PIO 0.01, GLIMP < 0.005 TRO = troglitazone ROSI = rosiglitazone PIO = pioglitazone GLIM = glimepiride Minamikawa J et al. J ClinEndocrinolMetab 1998; Koshiyama H et al. J ClinEndocrinolMetab2001; Sidhu JS et al. ArteriosclerThrombVascBiol2004;Langenfeld MR et al. Circulation 2005.

  8. † † † TRO* TRO PIO ROSI 0 -10 -20 Reduction over 6 months (%) -30 -39 -43 -40 P < 0.0001 -50 P < 0.0001 -54 -50 P < 0.0001 P = 0.03 -60 Neointimalarea Neointimalarea Neointimalarea Restenosis Endpoint TZDs consistently reduce restenosis after coronary stenting in patients with diabetes * vs diet † vs other anti-diabetic therapy TRO = troglitazone ROSI = rosiglitazone PIO = pioglitazone Takagi T et al. J Am Coll Cardiol 2000; Takagi T et al. Am J Cardiol 2002; Takagi T et al. Am Heart J 2003; Choi D et al. Diabetes Care 2004.

  9. Summary of effects of PPAR agonists on endothelial dysfunction in diabetes • Stimulates EC Nitric Oxide Release • Ameliorates EC Activation • Attenuates the Glucose-DAG-PKCb pathway • Clinical studies in diabetic & nondiabetic patients • Affects contractile, inflammatory & thrombotic dimensions of endothelial dysfunction

More Related