Elsevier

Redox Biology

Volume 20, January 2019, Pages 87-97
Redox Biology

Fenofibrate improves vascular endothelial function and contractility in diabetic mice

https://doi.org/10.1016/j.redox.2018.09.024Get rights and content
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Highlights

  • Fenofibrate improves diabetic endothelial function is via PPAR/LKB1/AMPK/eNOS signal.

  • Fenofibrate reduces diabetic endothelial contractility is via NF-κB/COX-2 pathway.

  • Diabetes-associated oxidative stress is attenuated by fenofibrate treatment.

Abstract

Fenofibrate, a peroxisome proliferator-activated receptors α (PPARα) agonist, reduces vascular complications of diabetic patients but its protective mechanisms are not fully understood. Here we tested the hypothesis that fenofibrate improves vascular endothelial dysfunction by balancing endothelium-dependent relaxation and contractility of the aorta in diabetes mellitus (DM). In streptozotocin-induced diabetic mice, eight weeks of fenofibrate treatment (100 mg/Kg/d) improved endothelium dependent relaxation in the macro- and microvessels, increased nitric oxide (NO) levels, reduced renal damage markers and effects of the vasoconstrictor prostaglandin. Levels of superoxide dismutase and catalase were both reduced and hydrogen peroxide was increased in vehicle-treated DM, but these changes were reversed by fenofibrate treatment. Vasodilation of the aorta after fenofibrate treatment was reversed by PPARα or AMPKα inhibitors. Western blots showed that fenofibrate treatment elevated PPARα expression, induced liver kinase B1 (LKB1) translocation from the nucleus to the cytoplasm and activated AMP-activated protein kinase-α (AMPKα), thus activating endothelial NO synthase (eNOS). Also, fenofibrate treatment decreased NF-κB p65 and cyclooxygenase 2 proteins in aortas. Finally, incubation with indomethacin in vitro improved aortic contractility in diabetic mice. Overall, our results show that fenofibrate treatment in diabetic mice normalizes endothelial function by balancing vascular reactivity via increasing NO production and suppressing the vasoconstrictor prostaglandin, suggesting mechanism of action of fenofibrate in mediating diabetic vascular complications.

Keywords

Diabetes
Fenofibrate
Endothelial dysfunction
Nitric oxide
Oxidative stress

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