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

نویسندگان

  • Vedat Tiyerili
  • Ulrich M Becher
  • Adem Aksoy
  • Dieter Lütjohann
  • Sven Wassmann
  • Georg Nickenig
  • Cornelius FH Mueller
چکیده

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.

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عنوان ژورنال:

دوره 12  شماره 

صفحات  -

تاریخ انتشار 2013