Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Science and Technology Office, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Clin Exp Pharmacol Physiol. 2021 Aug;48(8):1150-1161. doi: 10.1111/1440-1681.13507. Epub 2021 May 25.
Mitochondria are key regulators of cell fate, maintaining self-stability by a fine-tuned quality-control network including mitophagy, biogenesis, fission and fusion processes. Myocardial mitochondria can be impaired by hypercholesterolemia. Statins, such as atorvastatin, are considered the cornerstone in the management of hypercholesterolaemia primarily due to their marked cholesterol-lowering ability. The direct effect of atorvastatin on myocardial mitochondria remains unclear. We aimed to explore whether atorvastatin could attenuate myocardial mitochondrial defects induced by high cholesterol, and whether cycloastragenol, a potent telomerase activator, could be used as a potential complementary bioactive compound for obesity and hypercholesterolaemia treatment. We found that atorvastatin at a low dose (3 mg/kg) did not reduce elevated serum cholesterol, but reversed cardiac remodelling and dysfunction in C57BL/6J mice fed with high-fat diet (HFD). Atorvastatin reversed the upregulated mitophagy, mitochondrial fission and fusion, accompanied by mitochondrial biogenesis activation in HFD-fed mice hearts. Mitochondrial structural impairments were attenuated by atorvastatin in HFD-fed mice and oxidized low-density lipoprotein (ox-LDL) exposed HL-1 cardiomyocytes. The depolarized mitochondrial membrane potential and increased mitochondrial oxygen consumption rates in ox-LDL exposed HL-1 cells were recovered by atorvastatin. Furthermore, atorvastatin co-treated with cycloastragenol had better effects on reducing body weight, improving cardiac remodelling and dysfunction, and protecting mitochondria in high cholesterol. Conclusively, low-dose atorvastatin exhibited a cholesterol-independent cardioprotective effect through improving the mitochondrial quality-control network and repairing mitochondrial ultrastructure in high cholesterol. Atorvastatin plus cycloastragenol supplement therapy has a better effect on treating obesity and hypercholesterolaemia.
线粒体是细胞命运的关键调节者，通过包括线粒体自噬、生物发生、分裂和融合过程在内的精细质量控制网络来维持自身稳定性。高胆固醇血症可损害心肌线粒体。他汀类药物，如阿托伐他汀，主要因其显著的降胆固醇能力而被认为是高胆固醇血症治疗的基石。阿托伐他汀对心肌线粒体的直接作用尚不清楚。我们旨在探讨阿托伐他汀是否可以减轻高胆固醇引起的心肌线粒体缺陷，以及是否可以将环黄芪醇（一种有效的端粒酶激活剂）用作肥胖和高胆固醇血症治疗的潜在补充生物活性化合物。我们发现，低剂量（3mg/kg）的阿托伐他汀不能降低升高的血清胆固醇，但可逆转高脂饮食喂养的 C57BL/6J 小鼠的心脏重构和功能障碍。阿托伐他汀逆转了高脂饮食喂养小鼠心脏中上调的线粒体自噬、线粒体分裂和融合，同时激活了线粒体生物发生。阿托伐他汀减轻了高脂饮食喂养小鼠的线粒体结构损伤和氧化型低密度脂蛋白（ox-LDL）暴露的 HL-1 心肌细胞中的氧化应激。ox-LDL 暴露的 HL-1 细胞中线粒体膜电位去极化和线粒体耗氧量增加被阿托伐他汀恢复。此外，阿托伐他汀与环黄芪醇联合治疗在降低体重、改善心脏重构和功能以及保护高胆固醇中的线粒体方面具有更好的效果。总之，低剂量阿托伐他汀通过改善线粒体质量控制网络和修复高胆固醇中的线粒体超微结构，表现出一种与胆固醇无关的心脏保护作用。阿托伐他汀加环黄芪醇补充治疗对肥胖和高胆固醇血症的治疗效果更好。
