氧化应激相关蛋白p66Shc和GDF1在砷介导的心脏毒性中的作用机制研究

项目名称： 氧化应激相关蛋白p66Shc和GDF1在砷介导的心脏毒性中的作用机制研究

项目编号： No.81470525

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陆彩玲

作者单位： 国家卫生健康委科学技术研究所

项目金额： 73万元

中文摘要： Shc家族成员p66Shc和TGF-β家族成员GDF1都与氧化应激相关，在胚胎发育和心脏功能中扮演重要作用。砷是一种广泛的环境污染物，具有胚胎发育和心脏毒性，我们前期研究表明砷通过上调p66shc和抑制GDF1的表达引起胚胎发育毒性，抗氧化剂叶酸能拮抗砷的细胞毒性，降低砷介导的p66shc表达和ROS升高，显著恢复GDF1的表达。然而砷调控p66shc和GDF1表达的机制以及其是否介导砷的心脏毒性效应尚需进一步研究。本项目拟以小鼠和细胞为模型，应用报告基因、染色质免疫沉淀、siRNA等技术，探讨p66shc对砷介导ROS 产生的调控作用，阐明砷对p66shc和GDF1的表达调控机制以及p66shc/ROS在砷抑制GDF1中的作用，明确p66shc/ROS和GDF1通路在砷介导心肌细胞毒性和心脏损伤中的作用，为探讨砷所致心脏毒性的发生提供新机制，为寻找有效防护措施提供新思路。

中文关键词： 心肌毒性；砷；ROS；p66Shc；GDF1

英文摘要： p66shc, a member of Shc family,contributes to mitochondrial ROS metabolism and regulating the mitochontrial apoptosis pathway. The expression of Growth/differentiation factor 1(GDF1),a transforming growth factor-βmember, is downregulated via ROS produced in mitochontria. Both p66shc and GDF1 play an important role in embryo development and cardiac remodeling. Arsenic contamination is a major worldwide public health problem and associated with abnormal embryo development and cardiotoxicity. Our data showed that arsenic increased intracellular ROS level,upregulated the expression of p66shc and stimulated its translocation into the mitochondrial intermembrane space, which mediated arsenic-induced embryonic retardation. On the other hand, arsenic impaired embryo development via down-regulating GDF1 expression. Furthermore, we found that antioxidant folic acid decreased the expression upregulation of p66shc and ROS level caused by arsenic, markedly rescued the expression of GDF1, and antagonized arsenic-mediated cytoxicity. However, the molecular mechanism underlying the expression change of both p66shc and GDF1 and their role in cardiotoxicity mediated by arsenic need to be further investigated. Based on these findings,we will use both mice and cardiomyocytes to examine the effect of p66shc on arsenic-mediated ROS production, clarify the molecular mechanism of the expression change of both p66shc and GDF1 with arsenic treatment and the relationship between p66shc,ROS and GDF1,confirm the role of p66shc-ROS-GDF1 in arsenic-mediated cardiotoxicity. These findings will provide important evidences for the prevention and treatments of arsenic-mediated cardiotoxicity.

英文关键词： cardiotoxicity;arsenic;ROS;p66Shc;GDF1