Wang Yuehong, Li Zizhuo, Zhang Yu, Yang Wei, Sun Jiantao, Shan Lina, Li Weimin
Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Department of Inpatient Abdominal Ultrasonography, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Oxid Med Cell Longev. 2016;2016:4528906. doi: 10.1155/2016/4528906. Epub 2015 Dec 1.
Long-term heavy alcohol consumption is considered to be one of the main causes of left ventricular dysfunction in alcoholic cardiomyopathy (ACM). As previously suggested, high-dose alcohol induces oxidation stress and apoptosis of cardiomyocytes. However, the underlying mechanisms are yet to be elucidated. In this study, we found that high-dose alcohol treatment stimulated expression and activity of Pin1 in mouse primary cardiomyocytes. While siRNA-mediated knockdown of Pin1 suppressed alcohol-induced mouse cardiomyocyte apoptosis, overexpression of Pin1 further upregulated the numbers of apoptotic mouse cardiomyocytes. We further demonstrated that Pin1 promotes mitochondria oxidative stress and loss of mitochondrial membrane potential but suppresses endothelial nitric oxide synthase (eNOS) expression in the presence of alcohol. Taken together, our results revealed a pivotal role of Pin1 in regulation of alcohol-induced mouse cardiomyocytes apoptosis by promoting reactive oxygen species (ROS) accumulation and repressing eNOS expression, which could be potential therapeutic targets for ACM.
长期大量饮酒被认为是酒精性心肌病（ACM）中左心室功能障碍的主要原因之一。如前所述，高剂量酒精会诱导心肌细胞氧化应激和凋亡。然而，其潜在机制尚待阐明。在本研究中，我们发现高剂量酒精处理可刺激小鼠原代心肌细胞中Pin1的表达和活性。虽然小干扰RNA（siRNA）介导的Pin1敲低可抑制酒精诱导的小鼠心肌细胞凋亡，但Pin1的过表达进一步上调了凋亡小鼠心肌细胞的数量。我们进一步证明，Pin1在有酒精存在的情况下会促进线粒体氧化应激和线粒体膜电位丧失，但会抑制内皮型一氧化氮合酶（eNOS）的表达。综上所述，我们的结果揭示了Pin1在通过促进活性氧（ROS）积累和抑制eNOS表达来调节酒精诱导的小鼠心肌细胞凋亡中起关键作用，这可能是ACM的潜在治疗靶点。
