AT1-receptor-deficiency induced atheroprotection in diabetic mice is partially mediated via PPARγ

OBJECTIVE: Peroxisome-proliferator–activated-receptor-γ (PPARγ) acts as a transcriptional regulator of multiple genes involved in glucose and lipid metabolism. In vitro studies showed that activated PPARγ suppresses AT1R-gene expression and vice versa. However, it has not yet been determined in vivo, whether AT1R-PPARγ-interactions play a relevant role in the pathogenesis of diabetic complications and specifically in accelerated atherosclerosis. METHODS AND RESULTS: ApoE(−/−) and ApoE(−/−)/AT1R(−/−)-mice were rendered diabetic by intraperitoneal injections of streptozotocin. Diabetic and non-diabetic ApoE(−/−)-mice were further randomized to receive the AT1R antagonist telmisartan, the selective PPARγ antagonist GW9662, telmisartan and GW9662 or vehicle for 18 weeks. Diabetic and non-diabetic ApoE(−/−)/AT1R(−/−)-mice were randomized to receive either GW9662 or vehicle. GW9662 treatment in diabetic ApoE(−/−) and diabetic ApoE(−/−)/AT1(−/−)-mice resulted in the highest elevation of fasting blood glucose levels, whereas telmisartan treatment and AT1 deficiency in ApoE(−/−)-mice showed the lowest fasting blood glucose levels. Diabetic ApoE(−/−)-mice displayed severe impairment of endothelial function, enhanced oxidative stress and increased atherosclerotic lesion formation. ApoE(−/−)/AT1R(−/−) and telmisartan-treated ApoE(−/−)-mice showed a significantly better endothelial function, decreased oxidative stress and reduced atherosclerotic lesion formation. Treatment of diabetic ApoE(−/−) and ApoE(−/−)/AT1R(−/−)-mice with the selective PPARγ antagonist GW9662 omitted the atheroprotective effects of AT1R deficiency or AT1 antagonism. CONCLUSION: Genetic disruption or pharmacological inhibition of the AT1R attenuates atherosclerosis and improves endothelial function in diabetic ApoE(−/−)-mice via the PPARγ pathway.