S100a8/9调控线粒体复合物I活性加剧心脏缺血再灌注损伤的机制研究

Myocardial ischemia reperfusion injury leads to a series of adverse cardiovascular events, but lack of effective monitoring and prevention strategies. Mitochondrial dysfunction is a major mechanism of ischemia reperfusion injury. Our preliminary work showed that serum S100a8/9 levels were significantly increased in acute myocardial infarction (AMI) patients with major adverse cardiovascular events after PCI operation compared to AMI patients with no adverse events. S100a9 gene deficiency or S100a9 neutralizing antibody therapy inhibited myocardial ischemia reperfusion injury and heart failure. Transcriptome sequencing of cardiomyocytes stimulated by recombinant S100a8/9 or PBS showed that S100a8/9 inhibits multiple mitochondrial complex I subunit expression. However, how does S100a8/9 increase and how does S100a8/9 regulate mitochondrial function and ischemic reperfusion injury? These key issues are still unclear. This subject will application of cardiac ischemia reperfusion animal models, clinical samples of AMI patients, S100a9 knockout mice and specific over-expression mouse，virus overexpression and drug intervention techniques to clarify 1) Mechanism of CXCR2+Ly6Ghigh cells mobilization and secretion of S100a8/9 under stimulation of ischemia reperfusion; 2): Mechanism of S100a8/9 regulating mitochondrial complex I activity and mitochondrial function leading to ischemia reperfusion injury; 3) Clinical value of S100a8/9 as a potential biomarker for monitoring incidence of major adverse cardiovascular events in AMI patients after PCI operation. This study will provide a new target for the early detection and prevention of myocardial ischemia reperfusion injury.

心脏缺血再灌注损伤导致心脏不良事件发生，但缺乏有效监测和防治策略。线粒体功能障碍是心脏缺血再灌注损伤的主要机制。我们前期工作发现：急性心梗（AMI）PCI术后发生不良心脏事件患者血清S100a8/9水平较无不良事件组升高，敲除或中和S100a9抑制缺血再灌注损伤，S100a8/9刺激心肌细胞转录组测序示S100a8/9抑制线粒体复合物I亚基表达，但S100a8/9如何升高进而调控线粒体功能促进缺血再灌注损伤等关键问题尚不清楚。本研究拟阐明：1）缺血再灌注刺激促进CXCR2+Ly6Ghigh细胞动员分泌S100a8/9的机制；2）S100a8/9调控线粒体复合物I活性和线粒体功能促进缺血再灌注损伤发生的机制；3）S100a8/9监测AMI患者PCI术后不良心脏事件发生的临床价值。本研究将为心脏缺血再灌注损伤的早期监测和防治提供新的靶标。

背景：心肌缺血/再灌注损伤（MI/R）是影响急性心肌梗死后介入/搭桥治疗效果的主要事件，目前临床上尚缺乏MI/R的有效干预措施。因此明确MI/R导致心脏损伤的分子机制，为临床防治提供潜在新靶点，具有重要科学意义及临床价值。.主要研究内容：我们通过对MI/R后不同时间点的小鼠心脏进行动态转录组分析，确定了S100a8/a9在MI/R早期快速升高；动物体内S100a9敲除及过表达实验证实S100a8/a9可加重MI/R损伤，并且转录组和功能研究显示S100a8/a9可引起心肌细胞线粒体呼吸功能障碍。机制研究发现，S100a8/a9通过抑制TLR4/ERK介导的PGC-1α/NRF1信号通路，下调线粒体复合物I亚基NDUFs的基因表达，进而抑制线粒体复合体I功能，使线粒体功能障碍，导致心肌细胞死亡，促进MI/R发生发展。S100a9中和抗体治疗能明显减缓MI/R损伤，改善心功能。临床注册研究中，在纵向队列中发现经皮冠脉血管成形术（PCI）后1天血清S100a8/a9水平升高与急性心肌梗死患者长期心血管不良事件发生显著相关。在多中心，独立的大队列中我们前瞻性发现，PCI术后S100a8/a9水平是短期和长期心衰事件的独立预测因子。以S100a8/a9为基础的风险分层方法在多中心验证队列中表现良好。.科学意义：综上，我们的研究揭示了S100a8/a9是心肌缺血/再灌注损伤潜在治疗靶点和预警标志物。靶向S100a8/a9信号通路可能是一种新的治疗干预方法。我们研究发表后，国际同行相继在《European Heart Journal》 和《Circulation》发表工作证实我们的发现。开始研发S100a8/a9检测试剂盒。