Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-γ-dependent activity

Experimental and clinical data support the notion that peroxisome proliferator-activated receptor gamma (PPAR gamma) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPAR gamma agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPAR gamma activation. We compared the effects of telmisartan, telrnisartan combined with GW9662 (a PPAR gamma antagonist), and losartan with no PPAR gamma activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NF kappa B) activation and tumor necrosis factor alpha. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPAR gamma activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of vascular PPAR gamma in db/db mice and this effect of telmisartan was cancelled by the coadministration of GW9662. Our data provided the first evidence indicating that PPAR gamma activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. PPAR gamma activity of telmisartan was involved in the normalization of vascular PPAR gamma downregulation in diabetic mice. Thus, telmisartan seems to exert vascular protective effects in hypertensive patients with diabetes. (C) 2011 Elsevier Inc. All rights reserved.