PINK1在阿霉素诱导心肌细胞凋亡中的作用及芍药苷保护机制的实验研究

项目名称： PINK1在阿霉素诱导心肌细胞凋亡中的作用及芍药苷保护机制的实验研究

项目编号： No.81460613

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李健哲

作者单位： 广西中医药大学

项目金额： 48万元

中文摘要： 阿霉素是一种有效的抗肿瘤抗生素，但在治疗过程中可出现累积性的心脏毒性，使其临床应用受到限制。心肌细胞凋亡在阿霉素诱发的心脏毒性中有着重要的作用，其机制与产生过量活性氧，导致线粒体功能紊乱有关。研究发现，特异表达于线粒体的PINK1对维持正常线粒体结构和功能是必需的，其缺失可导致线粒体功能受损。芍药苷是从芍药根中提取的一种活性成分，我们前期研究证实，芍药苷可通过抑制活性氧的产生对阿霉素诱导的心肌细胞凋亡具有保护作用，但其确切机制尚不明确。基于PINK1表达异常可导致线粒体功能受损和阿霉素诱导的线粒体功能障碍在其心脏毒性中有着重要的作用，本项目拟证实PINK1在阿霉素诱导心肌细胞凋亡中的作用。在此基础上，探讨芍药苷对阿霉素诱导的心肌细胞凋亡是否具有保护作用，其机制是否与抑制活性氧的产生，进而调节PINK1的表达，改善线粒体功能有关。本项目将为阿霉素对心脏的损伤机制提供新的解释和药物治疗新靶点。

中文关键词： PINK1；阿霉素；线粒体；活性氧；芍药苷

英文摘要： Doxorubicin is an effective antitumor antibiotic. Unfortunately, its clinical application is limited because of cumulative cardiotoxicity. Many studies support that cardiomyocyte apoptosis plays an important role in doxorubicin-induced cardiotoxicity, which is closely related to mitochondrial dysfunction by excessive generation of reactive oxygen specise (ROS). It has been reported that PINK1, which is exclusively expressed in mitochondria, is indispensable for the normal structure and function of mitochondria. The loss of PINK1 will result in mitochondrial dysfunction. Paeoniflorin is a major active component isolated from the root of Paeonia lactiflora Pall. Our pilot study demonstrated that paeoniflorin was able to protect myocardial cell from doxorubicin-induced apoptosis by inhibiting ROS production, but the exact mechanism is still unclear. Since the abnormal expression of PINK1 will lead to mitochondrial dysfunction, and mitochondrial dysfunction plays an important role in doxorubicin-induced cardiotoxicity, we therefore investigate the roles of PINK1 in doxorubicin-induced cardiomyocyte apoptosis in the present project. On this basis, we will further investigate that whether paeoniflorin has a protective effect on cardiomyocyte apoptosis induced by doxorubicin, and whether the protective mechanism is related to improving mitochondrial function through regulation of PINK1 expression involving a mechanism of decreasing ROS production. This project will provide a new insight and drug target for doxorubicin-induced myocardial injury.

英文关键词： PTEN-inducible kinase 1;doxorubicin;mitochondria;reactive oxygen species;peoniflorin