Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Physical Therapy, Faculty of Allied Health Science, University of Phayao, Phayao, 56000, Thailand.
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.
Eur J Pharmacol. 2020 Sep 15;883:173347. doi: 10.1016/j.ejphar.2020.173347. Epub 2020 Jul 8.
Long-term high-fat diet consumption causes obese-insulin resistance and cardiac mitochondrial dysfunction, leading to impaired left ventricular (LV) function. Atorvastatin effectively improved lipid profiles in obese patients. However, inadequate reduction in low density lipoprotein cholesterol (LDL-C) level was found. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor effectively reduced LDL-C levels. We hypothesized that this PCSK9 inhibitor has a greater efficacy in attenuating cardiometabolic impairments than atorvastatin in obese-insulin resistant rats. Female rats were fed with either a high fat or normal diet for 12 weeks. High fat diet fed rats (HFD) were then divided into 3 groups and were given vehicle, atorvastatin (40 mg/kg/day; s.c.), or PCSK9 inhibitor (4 mg/kg/day; s.c.) for additional 3 weeks. The metabolic parameters, cardiac and mitochondrial function and [Ca] transients were determined. HFD rats developed obese-insulin resistance as indicated by increased plasma insulin and HOMA index. Although high-fat diet fed rats treated with vehicle (HFV) rats had markedly impaired LV function as indicated by reduced %LVFS, impaired cardiac mitochondrial function, and [Ca] transient regulation, these impairments were attenuated in high-fat diet fed rats treated with atorvastatin (HFA) and high-fat diet fed rats treated with PCSK9 inhibitor (HFP) rats. However, these improvements were greater in HFP rats than HFA rats. Our findings indicated that the PCSK9 inhibitor exerted greater cardioprotection than atorvastatin through improved mitochondrial function in obese-insulin resistant rats.
长期高脂肪饮食摄入可导致肥胖型胰岛素抵抗和心脏线粒体功能障碍，从而损害左心室（LV）功能。阿托伐他汀可有效改善肥胖患者的血脂谱。然而，低密度脂蛋白胆固醇（LDL-C）水平的降低并不充分。前蛋白转化酶枯草溶菌素/激肽释放酶 9（PCSK9）抑制剂可有效降低 LDL-C 水平。我们假设这种 PCSK9 抑制剂在肥胖型胰岛素抵抗大鼠中比阿托伐他汀更能减轻心脏代谢损伤。雌性大鼠接受高脂肪或正常饮食喂养 12 周。然后，将高脂肪饮食喂养的大鼠（HFD）分为 3 组，分别给予载体、阿托伐他汀（40mg/kg/天；皮下注射）或 PCSK9 抑制剂（4mg/kg/天；皮下注射），持续 3 周。测定代谢参数、心脏和线粒体功能以及[Ca]瞬变。HFD 大鼠表现出肥胖型胰岛素抵抗，表现为血浆胰岛素和 HOMA 指数增加。尽管给予载体的高脂肪饮食喂养的大鼠（HFV）的 LV 功能明显受损，表现为%LVFS 降低、心脏线粒体功能受损和[Ca]瞬变调节受损，但这些损伤在阿托伐他汀治疗的高脂肪饮食喂养的大鼠（HFA）和 PCSK9 抑制剂治疗的高脂肪饮食喂养的大鼠（HFP）中得到了减轻。然而，HFP 大鼠的这些改善大于 HFA 大鼠。我们的研究结果表明，PCSK9 抑制剂通过改善肥胖型胰岛素抵抗大鼠的线粒体功能，发挥了比阿托伐他汀更强的心脏保护作用。
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