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AT1-receptor-deficiency induced atheroprotection in diabetic mice is partially mediated via PPARγ
Vedat Tiyerili1, Ulrich M Becher, Adem Aksoy
1Medizinische Klinik und Poliklinik II, Innere Medizin, Universitätsklinikum Bonn, Sigmund Freud Str, 25, 53105, Bonn, Germany. Vedat.Tiyerili@ukb.uni-bonn.de
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.
Insights
In vivo, blocking the angiotensin II type 1 receptor (AT1R) pathway reduces atherosclerosis in diabetic mice. This protective effect is mediated by peroxisome-proliferator-activated-receptor-γ (PPARγ), highlighting a key interaction in diabetic complications.
Area of Science:
- Cardiovascular Research
- Metabolic Diseases
- Molecular Biology
Background:
- Peroxisome-proliferator-activated-receptor-γ (PPARγ) regulates genes in glucose and lipid metabolism.
- In vitro, PPARγ activation suppresses angiotensin II type 1 receptor (AT1R) gene expression, and vice versa.
- The in vivo relevance of AT1R-PPARγ interactions in diabetic complications, particularly atherosclerosis, remains unclear.
Purpose of the Study:
- To investigate the in vivo role of AT1R-PPARγ interactions in the development of accelerated atherosclerosis in diabetic mice.
- To determine if genetic or pharmacological inhibition of AT1R influences atherosclerosis and endothelial function via the PPARγ pathway.
Main Methods:
- ApoE-/- and ApoE-/-/AT1R-/- mice were made diabetic using streptozotocin.
- Mice received telmisartan (AT1R antagonist), GW9662 (PPARγ antagonist), both, or vehicle for 18 weeks.
- Endothelial function, oxidative stress, and atherosclerotic lesion formation were assessed.
Main Results:
- Telmisartan treatment and AT1R deficiency lowered blood glucose and reduced atherosclerosis, improved endothelial function, and decreased oxidative stress in diabetic mice.
- PPARγ antagonist GW9662 abolished the atheroprotective effects of AT1R deficiency or antagonism.
- GW9662 treatment elevated blood glucose levels significantly.
Conclusions:
- Genetic or pharmacological inhibition of AT1R attenuates atherosclerosis in diabetic ApoE-/- mice.
- The protective effects are mediated through the PPARγ pathway.
- Targeting the AT1R-PPARγ axis may offer therapeutic potential for diabetic atherosclerosis.
