Department of Cardiovascular Medicine, Jiulongpo District People's Hospital, Chongqing, China.
Department of Neurology, Jiulongpo District People's Hospital, Chongqing, China.
Braz J Med Biol Res. 2020 Jan 24;53(2):e8793. doi: 10.1590/1414-431X20198793. eCollection 2020.
Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.
阿利克仑（ALS）以其降压特性而闻名。然而，ALS 潜在的分子机制和抗肥厚作用尚未得到充分阐明。本研究旨在通过体内和体外心肌肥厚模型研究 ALS 在哺乳动物雷帕霉素靶蛋白（mTOR）和细胞凋亡信号中的作用。通过用异丙肾上腺素（5mg·kg-1·day-1）处理 4 周诱导大鼠心肌肥厚模型，并用或不用 20mg·kg-1·day-1 的 ALS 处理。通过 RT-qPCR 测定肥大、纤维化和凋亡标志物的表达。通过 Western blot 分析测定凋亡标志物 mTOR 和 p-mTOR 的蛋白表达。通过 MTS 测定法监测 H9C2 细胞的增殖。通过流式细胞术分析细胞凋亡。在体内，异丙肾上腺素处理的大鼠表现出更差的心脏功能，而 ALS 治疗逆转了这些功能障碍，这与 p-mTOR、Bcl-2、Bax 和 cleaved caspase-3 表达以及凋亡细胞数量的变化有关。在体外，Ang II 给药显著抑制 H9C2 心肌细胞活力并诱导心肌肥厚，但 ALS 逆转了 Ang II 诱导的 H9C2 心肌细胞肥大和死亡。此外，Ang II 触发肥厚心肌细胞中 mTOR 和细胞凋亡途径的激活，而 ALS 处理抑制了这种激活。这些结果表明，ALS 通过抑制心肌细胞中 mTOR 和细胞凋亡途径缓解心肌肥厚。
