Hao Jie, Du Hong, Liu Fan, Lu Jing-Chao, Yang Xiu-Chun, Cui Wei
Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China.
Exp Ther Med. 2019 Mar;17(3):2143-2151. doi: 10.3892/etm.2019.7212. Epub 2019 Jan 29.
Oxidative stress and mitochondrial dysfunction are considered to be activators of apoptosis and serve a pivotal role in the pathogenesis of myocardial ischemia-reperfusion (MI/R) injury. Apurinic/apyrimidinic endonuclease/redox factor 1 (APE1) is a multifunctional protein that processes the cellular response to DNA damage and oxidative stress. Little is known about the role of APE1 in the pathogenesis of MI/R injury. The aim of the present study was to investigate the effects of APE1 on hypoxia-reoxygenation (H/R)-induced H9c2 cardiomyocyte injury and the underlying mechanism responsible. It was demonstrated that H/R decreased cell viability and increased lactic dehydrogenase (LDH) release, as well as reducing APE1 expression in H9c2 cells. However, APE1 overexpression induced by transfection with APE1-expressing lentivirus significantly increased H9c2 cell viability, decreased LDH release, decreased apoptosis and reduced caspase-3 activity in H/R-treated H9c2 cells. APE1 overexpression ameliorated the H/R-induced increases in reactive oxygen species and NAPDH oxidase expression, as well as the decreases in superoxide dismutase activity and glutathione expression. Furthermore, APE1 overexpression increased mitochondrial membrane potential and ATP production, stabilized electron transport chain activity (as illustrated by increased NADH-ubiquinone oxidoreductase, succinate dehydrogenase, coenzyme Q-cytochrome c oxidoreductase and cytochrome c oxidase activities) and decreased the ratio of B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 in H/R, improving mitochondrial dysfunction. In conclusion, the results of the present study suggest that APE1 alleviates H/R-induced injury in H9c2 cells by attenuating oxidative stress and ameliorating mitochondrial dysfunction. APE1 may therefore be used as an effective treatment for MI/R injury.
氧化应激和线粒体功能障碍被认为是细胞凋亡的激活剂，在心肌缺血再灌注（MI/R）损伤的发病机制中起关键作用。脱嘌呤/脱嘧啶内切核酸酶/氧化还原因子1（APE1）是一种多功能蛋白，参与细胞对DNA损伤和氧化应激的反应。目前关于APE1在MI/R损伤发病机制中的作用知之甚少。本研究旨在探讨APE1对缺氧复氧（H/R）诱导的H9c2心肌细胞损伤的影响及其潜在机制。结果表明，H/R降低了H9c2细胞的活力，增加了乳酸脱氢酶（LDH）释放，并降低了APE1的表达。然而，通过转染表达APE1的慢病毒诱导的APE1过表达显著提高了H9c2细胞的活力，降低了LDH释放，减少了细胞凋亡，并降低了H/R处理的H9c2细胞中caspase-3的活性。APE1过表达改善了H/R诱导的活性氧和NAPDH氧化酶表达的增加，以及超氧化物歧化酶活性和谷胱甘肽表达的降低。此外，APE1过表达增加了线粒体膜电位和ATP生成，稳定了电子传递链活性（如NADH-泛醌氧化还原酶、琥珀酸脱氢酶、辅酶Q-细胞色素c氧化还原酶和细胞色素c氧化酶活性增加所示），并降低了H/R中B细胞淋巴瘤2相关X蛋白/B细胞淋巴瘤2的比值，改善了线粒体功能障碍。总之，本研究结果表明，APE1通过减轻氧化应激和改善线粒体功能障碍减轻H/R诱导的H9c2细胞损伤。因此，APE1可能作为MI/R损伤的有效治疗手段。
