Abstract 17084: PPARdelta-SIRT1 Interaction Protects Endothelial Function in Diabetic Mice
Introduction: Recent evidence highlights the therapeutic potential of peroxisome proliferator-activated receptor δ (PPARδ) agonists in the regulation of cardiovascular function. In addition, SIRT1 may be a novel therapeutic target for both metabolic and cardiovascular disorders. However, the effect and interaction of PPARδ and SIRT1-mediated protection of endothelial function in diabetes and obesity remain unclear. Hypothesis: The present study investigates whether PPARδ-SIRT1 interaction plays a key role in preserving endothelial function in diabetic and obese mice.
Methods: PPARδ wild-type and knockout (KO) mice, endothelial cell (EC)-specific SIRT1 mutant mice, db/db and db/m+, and C57BL/6 mice were used, and fed with normal chow or high fat diet. Vascular reactivity was studied in wire and pressure myographs. Nitric oxide (NO) and reactive oxygen species (ROS) production were measured, and en face immunofluorescence of aortic endothelium was performed.
Results: SIRT1 activators CAY10602 and resveratrol improved endothelium-dependent relaxations (EDRs) in ex vivo culture of isolated aortae from db/db mice or high-glucose treated aortae, and also in vivo in diabetic mice, accompanied by increased eNOS phosphorylation and NO production, while ROS production was reduced in primary ECs and aortic endothelium. Such beneficial effects were absent in EC-specific SIRT1 mutant mice, and reversed by SIRT1 inhibitor sirtinol and PPARδ antagonist GSK0660. In EC-specific SIRT1 mutant mice, EDRs in aortae and flow-mediated dilatation in mesenteric resistance arteries were reduced. Importantly, the effect of PPARδ agonist GW1516 to improve endothelial function was attenuated in SIRT1 mutant mice. On the other hand, the effects of CAY10602 and resveratrol were also diminished in PPARδ KO mice. In addition, resveratrol and CAY10602 up-regulated the PPARδ-mediated transcription in ECs while SIRT1 was down-regulated in PPARδ KO mice.
Conclusions: Our novel findings suggest a functional and molecular interaction between SIRT1 and PPARδ in the regulation of endothelial function in diabetes, supporting an active role of SIRT1 and PPARδ as potential targets in the prevention and alleviation of diabetes- and obesity-related vasculopathy.
- © 2012 by American Heart Association, Inc.