Fenofibrate Improves Vascular Contractility and Endothelial Function in Diabetic Mice

Aim: To exam the hypothesis that fenofibrate improves vascular endothelial dysfunction via balancing endothelium-dependent relaxation and constriction of aorta in diabetic mice. Methods: The streptozotocin-induced diabetic mice were treated with fenofibrate (100 mg/Kg/d, 8 weeks). The responses were assessed from serum and aortic parameters, vascular reactivity by wire myograph and aortic protein expression of endothelial nitric oxide synthase (eNOS), peroxisome proliferator-activated receptor α (PPARα), AMP-activated protein kinase-α (AMPKα) and liver kinase B1 (LKB1) and cyclooxygenase-2 (COX-2) in control and diabetic mice given placebo or fenofibrate. Results: Comparing with the control mice (12.2±2.0 μmol/L), serum creatinine increased by 114.8% in diabetic mice (26.2±2.0 μmol/L) and by 66.2% in fenofibrate-treated diabetic mice (21.6±2.8 μmol/L, p<0.01). NO level in aorta was 49.5±8.2 (μmol/g) in diabetic mice and 71.7±5.2 (μmol/g) in fenofibrate-treated diabetic mice (p<0.01). Compared with placebo-treated diabetic group, phosphorylated-eNOS protein in aorta was 3.6±1.0 fold higher (p<0.01) and endothelium-dependent relaxation was increased in fenofibrate-treated diabetic mice (p<0.01). The aorta vasodilation by fenofibrate treatment was reversed with PPARα inhibitor or AMPKα inhibitor. Fenofibrate treatment elevated PPARα expression, subsequently induced LKB1 translocation from nucleus to cytoplasm to activate AMPKα, thus activated eNOS in diabetic aorta (p<0.01). Fenofibrate treatment reduced vascular contractility and expression of COX-2 in aorta from diabetic mice(p<0.01). Prostaglandin E2 and thromboxane A2 were 174.9±16.4 and 128.9±4.4 (pg/ml) in diabetic mice, and reduced to 142.7±14.1 and 105.9±5.7 (pg/ml) in fenofibrate-treated mice (p<0.01). Conclusion: Fenofibrate treatment in diabetic mice normalizes endothelial function by balancing vascular reactivity via increasing NO production and suppressing vasoconstrictor prostaglandin. Our results suggest that implication of fenofibrate as a putative mediator of diabetic vascular complications.