转录因子Meis1调控心肌梗死后心律失常的机制——Meis1与离子通道重构

心肌梗死是最常见的心血管疾病之一，梗死边缘区心肌因离子通道失衡而引起电重构，是导致心律失常和心源性猝死发生的重要原因之一。如何抑制心肌梗死后心肌电重构及心源性猝死的发生是目前心律失常研究领域的难点。我们前期研究发现转录因子Meis1在梗死边缘区表达明显下调，因此推测Meis1是一个新的与心律失常发生相关的转录因子，但其具体调控机制有待阐明。本项目中我们提出假设：心肌梗死时Meis1在转录水平抑制钠、钙和钾等离子通道基因表达，引起心肌离子通道重构和电重构，增加心律失常易感性。本课题拟运用Meis1基因敲除小鼠及心梗动物模型、膜片钳等分子生物学技术验证:1）Meis1是否调控梗死边缘区心肌钠、钙和钾离子通道重构；2）引起心肌梗死时Meis1表达下调的上游调控因子；3）Meis1能否成为防治心肌梗死后心肌电重构和心律失常的新靶点。本研究将为临床预防心肌梗死后心律失常及心源性猝死的发生提供新思路。

Myocardial infarction (MI) is the most common cardiovascular disease. Ion channels remodeling occurs in MI and triggers malignant arrhythmias such as ventricular tachycardia and sudden cardiac death. How to prevent and treat electrical remodeling and arrhythmias in MI is a key research topic. In our preliminary study, we found that transcription factor Meis1 was significantly decreased in myocardium of the peri-infarcted zone (PIZ)，therefore we speculated that Meis1 is an important regulator associated with arrhythmias in MI, but the detailed mechanisms have not been elucidated. Accordingly, we propose a hypothesis that reduction of Meis1 in MI transcriptionally regulates sodium, calcium and potassium channels expression and cause ion channel remodeling and electrical remodeling, and subsequently increasing the susceptibility of infarcted hearts to arrhythmia. This study will employ Meis1 knockout mouse, Patch-clamp and molecular biological technique, etc. to determine if Meis1 is involved in cardiac sodium, calcium and potassium channels remodeling, further clarify the molecular mechanisms of Meis1 reduction in infarcted myocardium, and identify if Meis1 will be a therapeutic target for the prevention and treatment of electrical remodeling and arrhythmias in MI. The proposed studies will provide new insights into the treatment of cardiac arrhythmias in MI and the prevention of sudden cardiac death.