PCSK9 regulates myocardial ischemia-reperfusion injury through parkin/pink1-mediated autophagy pathway
PCSK9 regulates myocardial ischemia-reperfusion injury through parkin/pink1-mediated autophagy pathway
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DOI：
10.1007/s13273-023-00352-3
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发表时间：
2023-03-24
影响因子：
1.7
通讯作者：
Li，Wei
中科院分区：
文献类型：
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作者：
Huang，Guangwei;Bao，Hailong;Li，Wei
目的探讨前蛋白转化酶枯草杆菌蛋白酶9（PCSK 9）介导的自噬在心肌缺血再灌注损伤（MIRI）中的作用。目的探讨心肌细胞自噬、凋亡、纤维化和炎症反应的关系，为心肌缺血/再灌注损伤的防治提供实验依据。采用酶联免疫吸附法（ELISA）测定血浆心肌肌钙蛋白T（cTnT）和肌酸激酶MB（CKMB）浓度。为了确定心肌梗死的大小，进行了TTC/EB染色。除鉴别心肌组织的病理变化外，还使用Masson三色染色和H&E染色鉴别病理变化。超声心动图检测心功能。Western blot检测Parkin、Pink 1蛋白及自噬相关标志物Beclin-1、p62、LC 3蛋白的表达。在心脏特异性PCSK 9敲低模型中，心脏自噬被显著抑制，而心脏特异性PCSK 9过表达促进心脏自噬。体内研究表明，当施用PCSK 9抑制剂时，心脏自噬显著减少。PCSK 9抑制剂可显著减少I/R诱导的细胞凋亡，改善心肌梗死面积和功能。机械地，PCSK 9抑制剂改善了心肌纤维化的程度，抑制了炎症的发展。ConclusionsOur结果表明，增加PCSK 9通过parkin/pink 1信号通路有助于I/R和H/R通过夸大过度自噬在再灌注/复氧。此外，PCSK 9抑制剂阻断了炎症的发展，并改善了心肌细胞大小、心肌功能和心肌纤维化。
ObjectivesThis study aimed at investigating the role of the proprotein convertase subtilisin/Kexin type 9 (PCSK9)-mediated autophagy on myocardial ischemia/reperfusion injury (MIRI). To determine the relationship between autophagy, apoptosis, fibrosis, and inflammation in the myocardium, to provide experience in preventing and treating the myocardial ischemia/reperfusion (I/R) injury.MethodsAn AC16 hypoxia-reoxygenation model and a rat myocardial ischemia–reperfusion model were established. The concentrations of cardiac troponin T (cTnT) and creatine kinase-MB (CKMB) in plasma were measured by ELISA. To determine the size of the myocardial infarction, TTC/EB staining was performed. In addition to identifying pathological changes in myocardial tissue, Masson’s trichrome stains and H&E stains were used to identify pathological changes. Echocardiography was employed to detect cardiac function. Western blot analysis was then performed to detect the protein expression of Parkin, Pink1, and markers associated with autophagy (Beclin-1, p62, LC3).ResultsA significant increase in PCSK9 was observed in the myocardium during H/R. In the cardiac-specific PCSK9 knockdown model, cardiac autophagy was significantly inhibited, whereas cardiac-specific PCSK9 overexpression promoted cardiac autophagy. In vivo studies have demonstrated a significant decrease in cardiac autophagy when the PCSK9 inhibitor was administered. Apoptosis induced by I/R was greatly decreased, and myocardial infarction size and function were both improved by PCSK9 inhibitors. Mechanistically, the PCSK9 inhibitor improved the degree of myocardial fibrosis and inhibited the development of inflammation.ConclusionsOur results demonstrated that increased PCSK9 via the parkin/pink1 signaling pathway contributes to I/R and H/R by exaggerating excessive autophagy during reperfusion/reoxygenation. In addition, the PCSK9 inhibitor blocked the development of inflammation and improved Infarct size, myocardial function, and myocardial fibrosis.