速效救心丸通过miR-193/ALKBH5/m6A/Beclin-1途径保护心肌缺血再灌注损伤的机制研究

血运重建是急性心梗的最佳干预手段，但心肌缺血再灌注损伤（MIRI）明显减少其临床获益，目前缺乏有效临床治疗措施。研究表明，m6A修饰可调控MIRI中心肌细胞的自噬，ALKBH5是m6A的去甲基化酶，Beclin-1则是再灌注阶段过度自噬发生的主要原因。本课题组前期临床和基础研究提示，速效救心丸可减少ACS患者PCI围术期和缺血再灌注大鼠心肌损伤，影响miR-193、ALKBH5及Beclin-1的表达。结合生信分析表明ALKBH5可能是miR-193的靶基因，由此我们提出“速效救心丸靶向miR-193调控ALKBH5介导的m6A甲基化修饰，通过下调Beclin-1表达抑制心肌细胞自噬，从而减轻MIRI”的科学假说。本项目拟结合体内、体外模型，采用RNA干扰或过表达等实验技术，明确miRNA调控m6A在速效救心丸抑制细胞自噬进而减少MIRI中的关键作用，为速效救心丸干预MIRI提供理论依据。

Revascularization is the best intervention for acute myocardial infarction. However, myocardial ischemia reperfusion injury (MIRI) significantly reduces its clinical benefits and currently lacks effective clinical treatment measures. Studies have shown that m6A modification can regulate the autophagy of cardiomyocytes in MIRI, while ALKBH5 is the demethylase of m6A, and Beclin-1 is the main cause of excessive autophagy in the reperfusion stage. Our previous clinical and basic researches suggest that Suxiao Jiuxin Pill (SJP) can reduce myocardial injury both in acute coronary syndrome (ACS) patients during perioperative percutaneous coronary intervention (PCI) and ischemia-reperfusion rats, and affect the expression of miR193, ALKBH5 and Beclin-1. Combined with bioinformatics software analysis, ALKBH5 may be a target gene of miR193. Therefore, we proposed the scientific hypothesis that "Suxiao Jiuxin Pill targets miR193 to regulate ALKBH5 mediated m6A methylation modification, further inhibit myocardial cell autophagy by down-regulating Beclin-1 expression, thereby reducing MIRI ". This project intends to combine in vivo and in vitro models and use experimental techniques such as RNA interference or overexpression to clarify the key role of miRNA regulation m6A in inhibiting autophagy and reducing MIRI by SJP, providing a theoretical basis for SJP intervention in MIRI.