三氧化二砷诱发致死性心律失常机制研究

项目名称： 三氧化二砷诱发致死性心律失常机制研究

项目编号： No.30873065

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 杜智敏

作者单位： 哈尔滨医科大学

项目金额： 28万元

中文摘要： 本项目通过在体、离体水平实验，采用激光共聚焦、膜片钳、Western blot、Real-time PCR等技术研究三氧化二砷诱发QT间期延长的分子机制并探索拮抗三氧化二砷心肌毒性的保护药物及其作用机制。本项目在国内外首次发现：1）三氧化二砷通过作用于钾、钙离子通道延长动作电位时程（APD）进而诱发长QT间期综合征。2）三氧化二砷能够上调转录因子SRF表达水平。3）MiRNA-1和miRNA-133参与了三氧化二砷诱发QT间期延长的重要过程。4）SRF能够调节miRNA-1和miRNA-133的表达水平。5）MiRNA-1和miRNA-133分别通过抑制Kv4.2,Kir2.1及Herg蛋白表达水平延长QT间期。6）染料木素对三氧化二砷产生的心肌毒性具有保护作用。本研究证实三氧化二砷通过调控SRF进而上调miRNA-1，miRNA-133的表达水平，转录后抑制相应离子通道靶蛋白表达，影响离子通道平衡最终诱发QT间期延长，此外本研究还发现染料木素对三氧化二砷诱发的心肌毒性具有保护作用。综上，本研究为防治三氧化二砷诱发致死性心律失常提供理论基础。

中文关键词： 三氧化二砷；长QT间期综合症；microRNA；离子通道；染料木素

英文摘要： In vivo and in vitro studies were carried out in the present project, and laser scanning confocal microscopy, path clamp, western blot,Real-time PCR technologies were employed to explore the potential molecular mechanisms of arsenic trioxide induced LQT syndrome, and to identify novel substances against the cardiac toxicity of arsenic trioxide. We firstly found that: 1)Arsenic trioxide regulated the function of calcium and potassium channels to prolong the action potential duration (APD) and lead to LQT syndrome. 2)Arsenic trioxide modulated the expression of SRF in LQT model. 3）MiRNA-1 and miRNA-133 were involved in the prolongation of QT interval induced by arsenic trioxide. 4)The level of miRNA-1 and miRNA-133 were downregulated by arsenic trioxide. 5) The levels of Kv4.2 , Kir2.1 and Herg were suppressed by miRNA-1 and miRNA-133 ,respectively. 6) Protective effect of genistein against arsenic trioxide induced cardiac toxicity was observed. Our research suggested that arsenic trioxide increased the expression of SRF and upregulated the level of miRNA-1 and miRNA-133 which post-transcriptionally inhibited the expression of corresponding ion channel proteins, disturbed the balance of ion channel and contributed to QT interval prolongation.In addition, we also found the protective effect of genistein against cardiac toxicity induced by arsenic trioxide. In summary, our study provided the rationale for prevention and cure of fatal arrhythmias caused by arsenic trioxide.

英文关键词： arsenic trioxide;SRF;miRNA;QT interval;genistein