PCSK9调控PINK1/Parkin介导的心肌线粒体自噬对缺血再灌注后无复流现象的影响及机制研究

急性心肌梗死PCI术中无复流明显降低了手术获益，其发生机制与心肌细胞缺血再灌注损伤密切相关。已知线粒体自噬过度可加重缺血再灌注损伤，而心肌细胞线粒体自噬对无复流的作用尚不明确。PCSK9是一种肝源性分泌蛋白，参与血脂调节。我们发现，PCSK9使AC16细胞缺氧/复氧模型p-AMPKα蛋白表达和自噬水平上调，并降低了线粒体膜电位，促进Parkin线粒体转位。我们推测“PCSK9可能通过调控心肌线粒体自噬，进而影响缺血再灌注后无复流现象”。本课题拟在人群水平观察血清PCSK9对PCI术后无复流的评估价值；观察体内模型缺血再灌注期间PCSK9与心肌线粒体自噬和无复流现象的变化规律与相关性；重点研究体内、体外模型AMPKα-PINK1/Parkin-SQSTM1信号通路与PCSK9调节线粒体自噬的相关性和作用机制。项目完成将为无复流现象的防治提供更多的治疗选择，基础理论研究的成果更具有临床实用性。

No-reflow during PCI in patients with acute myocardial infarction significantly reduces the benefit of surgery, and its mechanism is closely related to myocardial ischemia-reperfusion injury. It is known that myocardial mitophagy can aggravate ischemia-reperfusion injury, and the effect of mitophagy on no-reflow is still unclear. PCSK9 is a hepatogenic secretory protein involved in lipid regulation. We found that PCSK9 increased the expression of p-AMPKα protein and autophagy level in AC16 cell hypoxia/reoxygenation model, decreased mitochondrial membrane potential and promoted Parkin mitochondrial translocation. We speculate that PCSK9 may affect the no-reflow phenomenon after ischemia-reperfusion by regulating myocardial mitochondrial autophagy. The purpose of this study is to observe the value of serum PCSK9 in evaluating no-reflux after PCI at population level; to observe the changes and correlation between PCSK9 and myocardial mitophagy and no-reflux during ischemia-reperfusion in vivo model; and emphasis is laid on the correlation and mechanism of AMPKα-PINK1/Parkin-SQSTM1 signaling pathway and PCSK9 regulating mitophagy in vivo and in vitro model. The completion of the project will provide more treatment options for the prevention and treatment of no-reflow phenomenon, and the results of basic theoretical research will be more practical in clinical practice.