Department of Physiology, School of Basic Medical Sciences, and Kidney Disease Center of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Redox Biol. 2019 Jan;20:87-97. doi: 10.1016/j.redox.2018.09.024. Epub 2018 Oct 1.
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.
非诺贝特是过氧化物酶体增殖物激活受体α（PPARα）激动剂，可减少糖尿病患者的血管并发症，但其保护机制尚未完全阐明。在这里，我们通过测试假设，即非诺贝特通过平衡糖尿病（DM）中大动脉的内皮依赖性松弛和收缩来改善血管内皮功能障碍。在链脲佐菌素诱导的糖尿病小鼠中，八周的非诺贝特治疗（100mg / kg / d）改善了大血管和微血管中的内皮依赖性松弛，增加了一氧化氮（NO）水平，降低了肾损伤标志物和血管收缩性前列腺素的作用。在车辆处理的 DM 中，超氧化物歧化酶和过氧化氢酶的水平均降低，而过氧化氢的水平增加，但这些变化被非诺贝特治疗所逆转。在用 PPARα或 AMPKα抑制剂处理后，主动脉的血管舒张作用被逆转。Western blot 显示，非诺贝特治疗可升高 PPARα表达，诱导肝激酶 B1（LKB1）从核转移到细胞质并激活 AMP 激活蛋白激酶-α（AMPKα），从而激活内皮型一氧化氮合酶（eNOS）。此外，非诺贝特治疗还降低了 NF-κB p65 和环氧化酶 2 蛋白在主动脉中的表达。最后，体外孵育吲哚美辛可改善糖尿病小鼠的主动脉收缩性。总的来说，我们的结果表明，非诺贝特治疗可通过增加 NO 产生和抑制血管收缩性前列腺素来平衡血管反应性，从而使糖尿病小鼠的内皮功能正常化，提示非诺贝特在介导糖尿病血管并发症中的作用机制。
