表儿茶素拯救As2O3诱发的LQT2的作用及机制研究

抗癌药物三氧化二砷（As2O3）临床应用时能够导致心室肌细胞中HERG通道蛋白表达减少诱发LQT2，易产生恶性心律失常。目前尚无有效的药物来拯救As2O3诱发的LQT2。我们在前期工作中发现：通过转染表达转录因子Sp1，能够抑制As2O3引起的HERG通道蛋白表达量减少；表儿茶素能够提高细胞内Sp1的表达量。因此，我们提出假设：表儿茶素能够通过提高心肌细胞内Sp1的表达量来上调HERG通道在细胞膜上的表达，拯救As2O3诱发的LQT2。为了证实这一假设，我们将通过HERG-HEK293细胞、豚鼠心室肌细胞和豚鼠大体模型，采用RT-PCR、Western Blot、膜片钳及心脏电生理仪等技术方法，从分子、细胞、组织以及动物水平探讨表儿茶素拯救As2O3诱发的LQT2的作用及机制。通过本课题将有助于深入了解获得性LQT2的发病机制，并为开发创新药物防治As2O3诱发的获得性LQT2奠定基础。

It has been reported that anti-cancer drug arsenic trioxide (As2O3) inhibits the HERG protein processing in the cell, which causes acquired LQT2 in clinical use. The delayed repolarization of the heart increases the risk of fatal cardiac arrhythmia. There is no agent to rescue LQT2 induced by As2O3. Interestingly, our previous studies showed that the transfection of Sp1 cDNA in HERG-HEK293 cells, increased the expression of HERG protein, which could recover the HERG deficiency induced by As2O3; epicatechin could increase the expression of transcription factor Sp1. Therefore, we propose that epicatechin may increase the expression of transcription factor Sp1, which is able to up-regulate HERG channel expression to rescue LQT2 induced by As2O3. To study the above hypothesis, we elucidate the effect and mechanism of epicatechin rescues As2O3-induced LQT2 in vitro and in vivo, which are evaluated using the technology of RT-PCR, western blot, patch clamp and cardiac electrophysiology. The study will have new insight into the pathogenesis of acquired LQT2 and development of innovative drug for treatment of acquired LQT2 induced by As2O3.