Abstract
ObjectivePeroxisome-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 resultsApoE−/− 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.ConclusionGenetic disruption or pharmacological inhibition of the AT1R attenuates atherosclerosis and improves endothelial function in diabetic ApoE−/−-mice via the PPARγ pathway.
Highlights
Diabetes mellitus is a leading cause of morbidity and mortality in western countries due to cardiovascular complications [1]
The metabolic abnormalities associated with diabetes lead to activation of the renin-angiotensinaldosterone system (RAAS) with a subsequent increase of angiotensin II (Ang II) and increased AT1-receptor (AT1R) activation [3,4]
Diabetic ApoE−/−-mice treated with telmisartan and diabetic ApoE−/−/AT1−/−-mice showed the lowest fasting blood glucose levels compared to the Diabetic ApoE−/− Vehicle (n = 8) Telmisartan (n = 8) Telmi + GW9662 (n = 7) GW9662 (n = 7) Diabetic ApoE/AT1−/− Vehicle (n = 6) GW9662 (n = 6) Non-diabetic ApoE−/−
Summary
Diabetes mellitus is a leading cause of morbidity and mortality in western countries due to cardiovascular complications [1]. It has been suggested that hyperglycaemia, insulin resistance, glycation of proteins, oxidative stress and inflammation may be related to atherogenesis in diabetes [2]. The metabolic abnormalities associated with diabetes lead to activation of the renin-angiotensinaldosterone system (RAAS) with a subsequent increase of angiotensin II (Ang II) and increased AT1-receptor (AT1R) activation [3,4]. The relevance of these mechanisms has not been determined in an in vivo model of diabetes. Whether interactions of AT1R and PPARγ play a key role in the pathogenesis of diabetes-induced atherosclerosis remains undetermined
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