6 - Resveratrol improves endothelial function in diabetic and obese mice through SIRT1-PPARδ

Abstract

SIRT1 activation reduces vascular oxidative stress, inhibits inflammatory responses, and retards cellular senescence in mouse models of diabetes. However, whether SIRT1 also plays a protective role in vascular dysfunction of diabetic and obese mice is not fully characterized. Previous work showed that PPARδ is beneficial in diabetic vascular dysfunction. Whether PPARδ is involved in the effect of SIRT1 on vascular endothelial function is unknown. We used mice with overexpression of endothelial cell-specific human SIRT1 (SIRT1-Tg) and dominant negative SIRT1 (SIRT1-mut) fed with normal chow and high fat diet to show expression of functional SIRT1 in endothelium protects against vascular dysfunction in diet-induced obese mice. Endothelial overexpression of SIRT1 improved endothelium-dependent dilation in aorta treated with risk factors including high glucose, angiotensin II, and lysophosphatidylcholine. Wild type (Ppard-wt) and PPARδ knockout (Ppard-mut) mice on high fat diet were treated with resveratrol. Resveratrol treatment improves endothelial function in Ppard-wt but not Ppard-mut mice. Experiments on isolated arteries ex vivo also showed that the effect of SIRT1 activator resveratrol or CAY10602 can be inhibited by PPARδ antagonist GSK0660. Resveratrol increased PPARδ transcriptional activity in endothelial cells. Results demonstrated here indicated that PPARδ contributes to the beneficial effect of SIRT1 against endothelial dysfunction in diabetic and obese mice. These results help to understand SIRT1-based strategy for treating vascular and metabolic dysfunction in the context of obesity and insulin resistance.