AQ-390靶向GSDMD减轻细胞焦亡缓解心肌缺血再灌注损伤的作用及机制研究

急性心肌梗死行再灌注治疗中可使可逆性缺血损伤转化为不可逆性再灌注损伤。最新研究表明炎症反应在心肌缺血再灌注损伤中起了非常关键的作用，其引起的细胞焦亡是细胞内新的一种程序性死亡方式。我们前期实验证实GSDMD介导的细胞焦亡加重心肌缺血再灌注损伤，故作为细胞焦亡执行蛋白的关键分子GSDMD可成为药物治疗的潜在靶点。我们在500万个小分子库中，基于分子对接的计算机虚拟筛选出的GSDMD潜在小分子抑制剂AQ-390。初步发现AQ-390可与GSDMD蛋白结合，并有效减少小鼠心肌梗死面积。基于此，本课题欲构建心肌缺血再灌注模型，从体内、外水平探究AQ-390减轻GSDMD介导的细胞焦亡发挥抗心肌缺血再灌注损伤的作用。进一步，揭示AQ-390与GSDMD结合的位点，阐明AQ-390对GSDMD生物学功能的作用机制，为心肌细胞缺血再灌注损伤的防治提供新的靶点及新药物，这将具有广阔的应用前景。

Reperfusion therapy for acute myocardial infarction can transform reversible ischemic injury into irreversible reperfusion injury. Recent researches suggest that inflammation plays a key role in myocardial ischemia-reperfusion injury. Pyroptosis induced by inflammation is a new programmed cell death which accelerates cell death. Our previous experiments confirmed that GSDMD-mediated cell pyroptosis aggravates myocardial ischemia-reperfusion injury.Therefore GSDMD, as a key molecule of cytopyroptosis executor protein, could become a potential target for drug therapy. We screened out the potential anti-GSDMD small molecule inhibitor AQ-390 based on computer simulation of molecular docking from the small molecule libraries including five million compounds.We found that AQ-390 could bind to GSDMD protein and reduced the area of myocardial infarction in mice. Based on the above results, we intend to construct myocardial ischemia-reperfusion model in vivo and in vitro to elucidate the protective effect of AQ-390 on GSDMD-mediated pyroptosis during myocardial ischemia-reperfusion injury. Furthermore, we plan to reveal the binding site of AQ-390 to GSDMD and demonstrate the mechanism of effect of AQ-390 on GSDMD. This study will find a new target for the prevention and treatment of myocardial ischemia reperfusion injury and provide a new drug, which will have a broad application prospects.