Pemafibrate, A Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator, Reduces Plasma Eicosanoid Levels and Ameliorates Endothelial Dysfunction in Diabetic Mice

Abstract

Aims: 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. Methods: 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. Results: 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 2 ( P ＜0.001), prostaglandin E 2 , leukotriene B 4 ( 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 12,14 -prostaglandin J 2 , 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. Conclusion: 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.