Impact of peroxisome proliferator-activated receptor γ on angiotensin II type 1 receptor-mediated insulin sensitivity, vascular inflammation and atherogenesis in hypercholesterolemic mice

INTRODUCTION: The angiotensin II type 1 receptor (AT1R) and the peroxisome proliferator-activated receptor γ (PPARγ) have been implicated in the pathogenesis of atherosclerosis. A number of studies have reported that AT1R inhibition or genetic AT1R disruption and PPARγ activation inhibit vascular inflammation and improve glucose and lipid metabolism, underscoring a molecular interaction of AT1R and PPARγ. We here analyzed the hypothesis that vasculoprotective anti-inflammatory and metabolic effects of AT1R inhibition are mediated by PPARγ. MATERIAL AND METHODS: Female ApoE(–/–)/AT1R(–/–) mice were fedwith a high-fat and cholesterol-rich diet and received continuous treatment with the selective PPARγ antagonist GW9662 or vehicle at a rate of 700 ng/kg/min for 4 weeks using subcutaneously implanted osmotic mini-pumps. Additionally, one group of female ApoE(–/–) mice served as a control group. After treatment for 4 weeks mice were sacrificed and read-outs (plaque development, vascular inflammation and insulinsensitivity) were performed. RESULTS: Using AT1R deficient ApoE(–/–) mice (ApoE(–/–)/AT1R(–/–) mice) we found decreased cholesterol-induced endothelial dysfunction and atherogenesis compared to ApoE(–/–) mice. Inhibition of PPARγ by application of the specific PPARγ antagonist GW9662 significantly abolished the anti-atherogenic effects of AT1R deficiency in ApoE(–/–)/AT1R(–/–) mice (plaque area as % of control: ApoE(–/–): 39 ±5%; ApoE(–/–)/AT1R(–/–): 17 ±7%, p = 0.044 vs. ApoE(–/–); ApoE(–/–)/AT1R(–/–) + GW9662: 31 ±8%, p = 0.047 vs. ApoE(–/–)/AT1R(–/–)). Focusing on IL6 as a pro-inflammatory humoral marker we detected significantly increased IL-6 levels in GW9662-treated animals (IL-6 in pg/ml: ApoE(–/–): 230 ±16; ApoE(–/–)/AT1R(–/–): 117 ±20, p = 0.01 vs. ApoE(–/–); ApoE(–/–)/AT1R(–/–) + GW9662: 199 ±20, p = 0.01 vs. ApoE(–/–)/AT1R(–/–)), while the anti-inflammatory marker IL-10 was significantly reduced after PPARγ inhibition in GW9662 animals (IL-10 in pg/ml: ApoE(–/–): 18 ±4; ApoE(–/–)/AT1R(–/–): 55 ±12, p = 0.03 vs. ApoE(–/–); ApoE(–/–)/AT1R(–/–) + GW9662: 19 ±4, p = 0.03 vs. ApoE(–/–)/AT1R(–/–)). Metabolic parameters of glucose homeostasis (glucose and insulin tolerance test) were significantly deteriorated in ApoE(–/–)/AT1R(–/–) mice treated with GW9662 as compared to vehicle-treated ApoE(–/–)/AT1R(–/–) mice. Systolic blood pressure and plasma cholesterol levels were similar in all groups. CONCLUSIONS: Genetic disruption of the AT1R attenuates atherosclerosis and improves endothelial function in an ApoE(–/–) mouse model of hypercholesterolemia-induced atherosclerosis via PPARγ, indicating a significant role of PPARγ in reduced vascular inflammation, improvement of insulin sensitivity and atheroprotection of AT1R deficiency.