National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, P.R. China.
Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
Mol Med Rep. 2020 Sep;22(3):1859-1867. doi: 10.3892/mmr.2020.11260. Epub 2020 Jun 19.
Age-related alterations in the renin-angiotensin-aldosterone system (RAAS) have been reported in the cardiovascular system; however, the detailed mechanism of the RAAS component mineralocorticoid receptors (MR) has not been elucidated. The present study aimed to investigate the associations between MR and cardiac aging in rats, as well as the regulatory effects of oxidative stress and mitochondrial abnormalities in the aging process. MR expression in the hearts of male Sprague‑Dawley rats aged 3 months (young rats) and 24 months (old rats) was evaluated in vivo. In addition, in vitro, H9C2 cells were treated with a specific MR antagonist, eplerenone, in order to investigate the molecular mechanism underlying the inhibition of myocyte aging process. The results demonstrated that MR expression was significantly higher in 24‑month‑old rat hearts compared with in 3‑month‑old rat hearts. These changes were accompanied by increased p53 expression, decreased peroxisome proliferator‑activated receptor γ coactivator‑1α expression, decreased mitochondrial renewal as assessed by electron microscopy, increased oxidative stress and decreased superoxide dismutase. In vitro, selective antagonism of MR partially blocked H2O2‑induced myocardial aging as assessed by p16, p21 and p53 expression levels and excessive reactive oxygen species (ROS) accumulation. These results indicated that increased MR expression may drive age‑related cardiac dysfunction via mitochondrial damage, increased ROS accumulation and an imbalanced redox state.
肾素-血管紧张素-醛固酮系统（RAAS）的年龄相关性改变已在心血管系统中得到报道；然而，RAAS 成分醛固酮受体（MR）的详细机制尚未阐明。本研究旨在探讨大鼠心脏中 MR 与心脏老化之间的关系，以及氧化应激和线粒体异常在老化过程中的调节作用。体内评估了雄性 Sprague-Dawley 大鼠 3 个月（幼鼠）和 24 个月（老年鼠）心脏中的 MR 表达。此外，在体外，用特异性 MR 拮抗剂依普利酮处理 H9C2 细胞，以研究抑制心肌老化过程的分子机制。结果表明，24 月龄大鼠心脏中的 MR 表达明显高于 3 月龄大鼠心脏。这些变化伴随着 p53 表达增加，过氧化物酶体增殖物激活受体 γ 共激活因子-1α 表达减少，电镜评估的线粒体更新减少，氧化应激增加，超氧化物歧化酶减少。在体外，MR 的选择性拮抗作用部分阻断了 H2O2 诱导的心肌老化，表现为 p16、p21 和 p53 表达水平升高和过量活性氧（ROS）积累。这些结果表明，MR 表达的增加可能通过线粒体损伤、ROS 积累增加和氧化还原状态失衡导致与年龄相关的心脏功能障碍。
