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.
Highlights
The endothelium and factors derived from endothelial cells are known to control vascular function, including the regulation of vascular tone [1,2]
Our results show that fenofibrate treatment reduced renal damage markers and plasma triglyceride levels, while there was no significant change in blood glucose and body weight between vehicle and fenofibrate-treated diabetic mice (DM)
Western blot results showed that fenofibrate treatment elevated peroxisome proliferator-activated receptors α (PPARα) expression, subsequently induced liver kinase B1 (LKB1) translocation from the nucleus to the cytoplasm to activate AMPKα and activated endothelial nitric oxide synthase (eNOS)
Summary
The endothelium and factors derived from endothelial cells are known to control vascular function, including the regulation of vascular tone [1,2]. Endothelial dysfunction is a hallmark of diabetes and contributes to macrovascular and microvascular complications associated with diabetes [3,4]. Vascular endothelial dysfunction has been characterized by reduced activity of endothelial nitric oxide synthase (eNOS), decreased generation of nitric oxide (NO) and increased generation of reactive oxygen species (ROS) [3,5]. There is an imbalance between endothelial-dependent vascular relaxation and constriction, which plays an important role in the development of pathologies associated with the disease [4,6,7]. Understanding the regulation of this imbalance may be important in preventing the development of diabetes-associated vasculopathies. Emerging clinal evidence has demonstrated that fenofibrate has a therapeutic potential in alleviating diabetes-associated vascular disease independently of its hypolipemic action.
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