Abstract 17733: PPARdelta Activation Protects Endothelial Function In Diabetic Mice via PI3K/Akt/eNOS Signaling Pathway

Abstract

Introduction: Recent evidence highlights therapeutic potentials of peroxisome proliferator-activated receptor-delta (PPARdelta) agonists to increase insulin sensitivity in diabetes. The significance of PPARdelta in the regulation of vascular function remains unclear. Hypothesis: The present study investigates whether PPARdelta activation improves endothelial function in type 2 diabetes. Methods: Vascular reactivity of mouse aortae was studied in myograph. Protein expression was detected by Western blotting. Nitric oxide (NO) production was measured by DAF-FM fluorescence using confocal microscopy. Results: PPARdelta agonists GW0742 and GW1516 improved endothelium-dependent relaxations in diabetic mouse aortae. PPARdelta agonists prevented high glucose-induced impairment of endothelium-dependent relaxations in aortae of wild type mice, but not in PPARdelta knockout mice. PPARdelta antagonist, PI3K inhibitors, or Akt inhibitor reversed the effect of PPARdelta activation on endothelial function. Western blotting showed an increased phosphorylation of eNOS and Akt upon PPARdelta activation under hyperglycaemia in primary endothelial cells (ECs) from mouse aortae. PPARdelta activation enhanced the NO production in ECs under hyperglycemia. Transient transfection with dominant-negative Akt inhibited the effect of GW1516 in ECs on NO production and eNOS and Akt phosphorylation. Chronic treatment with GW1516 (5 mg/kg/day for one week) improved endothelium-dependent relaxation in db/db mice, and diet-induced obese PPARdelta wild type mice, but not in PPARdelta knockout mice. Conclusions: The present study demonstrates an endothelial protective effect of PPARdelta activation in diabetes through PI3K/Akt signaling which increases eNOS activity, suggesting the potential of PPARdelta agonists in the treatment of diabetic vasculopathy.