Vascular effects of PPAR activation: Endothelial function
Potential vascular benefits of PPAR activation Cariou B et al. Br J Diabetes Vasc Dis. 2005;5(3): PPAR agonists Thrombosis Plaque stability Cell recruitment and activation Inflammatory response Vasoconstriction Cell migration Foam cell formation Cholesterol efflux Atherogenesis Improved substrate metabolism
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:
PPAR activation and endothelial function Campia U et al. Circulation 2006; 113:
Endothelial dysfunction by TNF -infusion NO dependent vasodilation ,61,86 Dosis serotonin (ng/100mlFAV/min) MC % change Pioglitazone +TNF (10ng/min/2h) Placebo +TNF (10ng/min/2h) Martens FM, Eur Heart J. 2006;27(13):1605-9
PPAR activation blunts progression of carotid atherosclerosis Langenfeld MR et al. Circulation. 2005;111: N = 173 with type 2 diabetes –0.04 –0.08 –0.12 –0.16 P < P < Carotid IMT (mm) Pioglitazone 45 mg Glimepiride 2.7 mg ns Weeks
TZDs impact carotid IMT Minamikawa J et al. J Clin Endocrinol Metab 1998; Koshiyama H et al. J Clin Endocrinol Metab 2001; Sidhu JS et al. Arterioscler Thromb Vasc Biol 2004;Langenfeld MR et al. Circulation TRO = troglitazone ROSI = rosiglitazone PIO = pioglitazone GLIM = glimepiride Study (year)Treatment Patients (Duration) IMT (mm) Minamikawa (1998) TRO 400 mg Usual care DM2 (6 mo) 0.08, TRO 0.03, Usual care P < Koshiyama (2001) PIO 30 mg Usual care DM2 (6 mo) 0.08, PIO 0.02, Usual care P < Sidhu (2004) ROSI 8 mg Placebo Stable CAD (48 wk) 0.01, ROSI 0.03, Placebo P = 0.03 Langenfeld (2005) PIO 45 mg GLIM 2.7 mg (mean) DM2 (6 mo) 0.05, PIO 0.01, GLIM P < 0.005
TZDs consistently reduce restenosis after coronary stenting in patients with diabetes 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 * vs diet † vs other anti-diabetic therapy TRO = troglitazone ROSI = rosiglitazone PIO = pioglitazone Neointimal area Restenosis Endpoint ††† P < P = TRO*TROPIOROSI Reduction over 6 months (%)
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