Fenofibrate improves vascular endothelial function and contractility in diabetic mice.

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.

• Authors: Nan Xu, Qin Wang, Shan Jiang, Qijing Wang, Weipeng Hu, Suhan Zhou, Liang Zhao, Lanyu Xie, Jianghua Chen, Anton Wellstein, En Yin Lai
• Journal: Redox biology (Redox Biol) Vol. 20 Pg. 87-97 (01 2019) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 30296701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers
• Hypolipidemic Agents
• Lipids
• NF-kappa B
• Peroxisome Proliferator-Activated Receptors
• Nitric Oxide
• Hydrogen Peroxide
• Nitric Oxide Synthase Type III
• Cyclooxygenase 2
• Fenofibrate

Topics

• Animals
• Biomarkers
• Cyclooxygenase 2 (metabolism)
• Diabetes Mellitus, Experimental (metabolism)
• Endothelium, Vascular (drug effects, metabolism)
• Fenofibrate (pharmacology)
• Hydrogen Peroxide (metabolism)
• Hypolipidemic Agents (pharmacology)
• Kidney (drug effects, metabolism)
• Lipids (blood)
• Male
• Mice
• Microvessels (drug effects, metabolism, physiopathology)
• Models, Biological
• NF-kappa B (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Oxidative Stress (drug effects)
• Peroxisome Proliferator-Activated Receptors (antagonists & inhibitors, metabolism)