The angiotensin receptor blocker, telmisartan, reduces and stabilizes atherosclerosis in ApoE and AT1aR double deficient mice

Daiju Fukuda, Soichiro Enomoto, Yoichiro Hirata, Ryozo Nagai, Masataka Sata
Biomedicine & Pharmacotherapy 2010, 64 (10): 712-7
The renin-angiotensin system (RAS) plays critical roles in the pathogenesis of atherosclerosis. Clinical studies demonstrate that pharmacological blockade of RAS with Angiotensin II type 1 receptor (AT1R) blockers (ARBs) is effective in the treatment of patients with cardiovascular diseases. Recent studies reported that telmisartan, an ARB, has a partial agonistic effect on peroxisome proliferator-activated receptor-gamma (PPAR-γ). The role of PPAR-γ-mediated signaling has been implicated in regulation of not only metabolic disorders but also atherosclerosis. Here, we investigated the effects of telmisartan, which is not related to AT1R blockade, using AT1aR and apolipoprotein E (ApoE) double-deficient (ApoE-/-AT1R-/-) mice in vivo. Both genetic ablation of AT1R in ApoE-deficient (ApoE-/-) mice and administration of telmisartan (10 mg/kg/day) to ApoE-/- mice for 20 weeks reduced the development of atherosclerosis (P<0.05, respectively). Telmisartan decreased lipid deposition (P<0.01) and increased collagen contents (P<0.05) in plaques in ApoE-/- mice. Administration of telmisartan to ApoE-/-AT1aR-/- mice also inhibited the progression of atherosclerosis in aorta (P<0.05) even in mice, which have no AT1aR genetically. Moreover, in these mice, telmisartan decreased macrophage accumulation and lipid deposition, and increased collagen contents in plaques in aortic root (P<0.05, respectively), indicating stabilization of plaques. Telmisartan-treated ApoE-/-AT1aR-/- mice showed lower body weight and higher plasma high-density lipoprotein levels compared with vehicle-treated mice (P<0.05, respectively). Telmisartan lowered systolic and diastolic blood pressure in ApoE-/-AT1aR-/- mice (P<0.01). These results suggest that telmisartan has protective effects on the development of atherosclerosis and metabolic disorders beyond AT1R blockade in ApoE-deficient mice.

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