PPARδ Activation Protects Endothelial Function in Diabetic Mice

Recent evidence highlights the therapeutic potential of peroxisome proliferator-activated receptor-delta (PPAR delta) agonists to increase insulin sensitivity hi diabetes. However, the role of PPAR delta in regulating vascular function is incompletely characterized. We investigate whether PPAR delta activation improves endothelial function in diabetic and obese mice. PPAR delta knockout (KO) and wild-type (WT) mice fed with high-fat diet and db/db mice were used as diabetic mouse models, compared with PPAR delta KO and WT mice on normal diet and db/m(+) mice. Endothelium-dependent relaxation (EDR) was measured by wire myograph. Flow-mediated vasodilatation (FMD) was measured by pressure myograph. Nitric oxide (NO) production was examined in primary endothelial cells from mouse aortae. PPAR delta agonist GW1516 restored EDRs in mouse aortae under high-glucose conditions or in db/db mouse aortae ex vivo. After oral treatment with GW1516, EDRs in aortae and FMDs in mesenteric resistance arteries were improved in obese mice in a PPAR delta-specific manner. The effects of GW1516 on endothelial function were mediated through phosphatidylinositol 3-kinase (PI3K) and Ala with a subsequent increase of endothelial nitric oxide synthase (eNOS) activity and NO production. The current study demonstrates an endothelial-protective effect of PPAR delta agonists in diabetic mice through PI3K/Akt/eNOS signaling, suggesting the therapeutic potential of PPAR delta agonists for diabetic vasculopathy. Diabetes 61:3285-3293, 2012