Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences.
Department of Cardio-Diabetes Medicine, Tokushima University Graduate School of Biomedical Sciences.
J Atheroscler Thromb. 2021 Dec 1;28(12):1349-1360. doi: 10.5551/jat.61101. Epub 2021 Mar 27.
Various pathological processes related to diabetes cause endothelial dysfunction. Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, on plasma eicosanoid levels and endothelial function in diabetic mice.
Diabetes was induced in 7-week-old male wild-type mice by a single injection of streptozotocin (150 mg/kg). Pemafibrate (0.3 mg/kg/day) was administered orally for 3 weeks. Untreated mice received vehicle. Circulating levels of eicosanoids and free fatty acids were measured using both gas and liquid chromatography-mass spectrometry. Endothelium-dependent and endothelium-independent vascular responses to acetylcholine and sodium nitroprusside, respectively, were analyzed.
Pemafibrate reduced both triglyceride and non-high-density lipoprotein-cholesterol levels (P＜0.01), without affecting body weight. It also decreased circulating levels of AA (P＜0.001), thromboxane B (P＜0.001), prostaglandin E, leukotriene B (P＜0.05), and 5-hydroxyeicosatetraenoic acid (P＜0.001), all of which were elevated by the induction of diabetes. In contrast, the plasma levels of 15-deoxy-Δ-prostaglandin J, which declined following diabetes induction, remained unaffected by pemafibrate treatment. In diabetic mice, pemafibrate decreased palmitic acid (PA) and stearic acid concentrations (P＜0.05). Diabetes induction impaired endothelial function, whereas pemafibrate ameliorated it (P＜0.001). The results of ex vivo experiments indicated that eicosanoids or PA impaired endothelial function.
Pemafibrate diminished the levels of vasoconstrictive eicosanoids and free fatty acids accompanied by a reduction of triglyceride. These effects may be associated with the improvement of endothelial function by pemafibrate in diabetic mice.
与糖尿病相关的各种病理过程会导致内皮功能障碍。源自花生四烯酸（AA）的类二十烷酸在血管调节中起作用。最近的研究表明，贝特类药物可减轻糖尿病患者的血管并发症。在这里，我们研究了过氧化物酶体增殖物激活受体α调节剂 pemafibrate 对糖尿病小鼠血浆类二十烷酸水平和内皮功能的影响。
通过单次注射链脲佐菌素（150mg/kg）诱导 7 周龄雄性野生型小鼠发生糖尿病。pemafibrate（0.3mg/kg/天）经口给药 3 周。未治疗的小鼠给予载体。使用气相和液相色谱-质谱联用技术分别测量循环类二十烷酸和游离脂肪酸的水平。分别分析乙酰胆碱和硝普钠引起的内皮依赖性和非内皮依赖性血管反应。
pemafibrate 降低了甘油三酯和非高密度脂蛋白胆固醇水平（P＜0.01），而不影响体重。它还降低了循环 AA（P＜0.001）、血栓素 B（P＜0.001）、前列腺素 E、白三烯 B（P＜0.05）和 5-羟二十碳四烯酸（P＜0.001）的水平，这些物质在糖尿病诱导后均升高。相比之下，糖尿病诱导后下降的 15-脱氧-Δ-前列腺素 J 的血浆水平不受 pemafibrate 治疗的影响。在糖尿病小鼠中，pemafibrate 降低了棕榈酸（PA）和硬脂酸浓度（P＜0.05）。糖尿病诱导损害了内皮功能，而 pemafibrate 改善了内皮功能（P＜0.001）。体外实验结果表明，类二十烷酸或 PA 损害了内皮功能。
pemafibrate 降低了血管收缩性类二十烷酸和游离脂肪酸的水平，同时降低了甘油三酯水平。这些作用可能与 pemafibrate 改善糖尿病小鼠的内皮功能有关。
