Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
Department of Medical Technology, Kawasaki College of Allied Health Professions, Okayama, Japan.
Cardiovasc Diabetol. 2020 Sep 26;19(1):149. doi: 10.1186/s12933-020-01132-2.
Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats.
Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated.
After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone.
Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.
他汀类药物通过降低低密度脂蛋白（LDL）胆固醇水平来抑制动脉粥样硬化的进展。新型选择性过氧化物酶体增殖物激活受体α调节剂 pemafibrate（K-877）有望降低他汀类药物治疗期间的残余危险因素，包括高甘油三酯（TGs）和低高密度脂蛋白（HDL）胆固醇。然而，他汀类药物加用 pemafibrate 是否能改善动脉粥样硬化的进展尚不清楚。本研究旨在评估匹伐他汀和 pemafibrate 联合治疗对高血压和胰岛素抵抗模型大鼠脂质谱和血管内皮功能的影响。
将 7 周龄雄性 Dahl 盐敏感（DS）大鼠分为以下 5 个治疗组（正常饮食（ND）加载体、高盐高脂饮食（HD）加载体、HD 加匹伐他汀（0.3mg/kg/天）、HD 加 pemafibrate（K-877）（0.5mg/kg/天）和 HD 加匹伐他汀和 pemafibrate 联合治疗），并治疗 12 周。在 19 周时，评估对乙酰胆碱反应的胸主动脉内皮依赖性舒张功能。
喂养 12 周后，与 ND-载体组相比，HD-载体组大鼠收缩压和总胆固醇水平明显升高。与载体治疗相比，匹伐他汀和 pemafibrate 联合治疗显著降低了收缩压、甘油三酯水平，包括总甘油三酯、乳糜微粒（CM）、极低密度脂蛋白（VLDL）、HDL-甘油三酯和胆固醇水平，包括总胆固醇、CM、VLDL 和 LDL-胆固醇。所有大鼠的胸主动脉环在预先用苯肾上腺素收缩后，乙酰胆碱均引起浓度依赖性舒张。与 ND-载体组相比，HD-载体组的舒张率明显降低。与 HD-载体组相比，HD-匹伐他汀和 pemafibrate 联合治疗组的舒张率显著增加，尽管单独使用任何一种药物都不能显著改善舒张率。Western blot 实验显示，与 HD-载体组相比，pemafibrate 组和 HD-匹伐他汀和 pemafibrate 联合组大鼠主动脉中磷酸化内皮型一氧化氮合酶蛋白的表达增加。然而，单独使用匹伐他汀并没有显著改变表达水平。
匹伐他汀和 pemafibrate 联合治疗改善了高血压和胰岛素抵抗模型大鼠的脂质谱和血管内皮功能。pemafibrate 作为他汀类药物的附加策略，可能有助于预防动脉粥样硬化的进展。
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