PCSK9 regulates myocardial ischemia–reperfusion injury through parkin/pink1-mediated autophagy pathway

• Published in: Molecular & cellular toxicology 2024, 20(2), , pp.367-376
• Main Authors: Huang, Guangwei, Bao, Hailong, Zhan, Peng, Lu, Xiyang, Duan, Zonggang, Xiong, Xinlin, Lin, Muzhi, Wang, Bing, An, Hongxin, Xiahou, Luanda, Zhou, Haiyan, Luo, Zhenhua, Li, Wei
• Format: Article
• Language: English
• Subjects: Apoptosis; Autophagy; Biomedical and Life Sciences; Cell Biology; Creatine; Creatine kinase; Echocardiography; Fibrosis; Heart; Heart attacks; Hypoxia; Inflammation; Ischemia; Kexin; Kinases; Life Sciences; Myocardial infarction; Myocardial ischemia; Myocardium; Original Article; Parkin protein; Pharmacology/Toxicology; Proprotein convertases; PTEN-induced putative kinase; Reperfusion; Signal transduction; Subtilisin; Troponin; Troponin T; 생물학
• ISSN: 1738-642X; 2092-8467
• DOI: 10.1007/s13273-023-00352-3

Objectives This 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. Methods An 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). Results A 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. Conclusions Our 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.