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

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Abstract

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.

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Availability of supporting data

All data, models, or code generated or used during the study are available from the corresponding author by request.

Code availability

Not applicable.

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Acknowledgement

This work was supported by a Research Grant of Shanghai University of Traditional Chinese Medicine and by National Natural Science Foundation grant funded by the China government (Grant/Award Number: 81303256). Following are results of study on the “ATP-Sensitive Potassium Channels Mediate the Cardioprotective Effect of Panax notoginseng Saponins against Myocardial Ischaemia–Reperfusion Injury and Inflammatory Reaction”.

Funding

This work was mainly supported by the Science and Technology Foundation of Health commission of Guizhou Province (Grant No. gzwkj2022-317、gzwkj2021-112); the National Natural Science Foundation of China (Nos. 82160086, 81960047); the Science and Technology Fund of Guizhou Provincial Health Department [qiankehepingtairencai-GCC [2022]040-, qiankehezhicheng [2019]2800]; the Health and Family Planning Commission of Guizhou Province (qianweijianhan [2021]160).

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Author notes

  1. Guangwei Huang and Hailong Bao have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Medicine, The Affiliated Hospital of Guizhou Medical University, NO. 28 Guiyi Street, Yunyan District,, Guiyang, 550004, Guizhou, People’s Republic of China

    Guangwei Huang, Hailong Bao, Xiyang Lu, Zonggang Duan, Xinlin Xiong, Muzhi Lin, Bing Wang, Hongxin An, Luanda Xiahou, Haiyan Zhou & Wei Li

  2. Department of Cardiovascular Medicine, Anshun City People’s Hospital, Anshun, 561000, Guizhou, People’s Republic of China

    Guangwei Huang & Peng Zhan

  3. Guizhou Medical University, Guiyang, 550004, Guizhou, People’s Republic of China

    Guangwei Huang, Hailong Bao, Xiyang Lu, Zonggang Duan, Xinlin Xiong, Muzhi Lin, Bing Wang, Hongxin An, Luanda Xiahou, Haiyan Zhou & Wei Li

  4. Department of Central Lab, Guizhou Provincial People’s Hospital, 83 East Zhongshan Road, Guiyang, 550002, Guizhou, People’s Republic of China

    Zhenhua Luo

  5. NHC Key Laboratory of Pulmonary Immune-Related Diseases, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China

    Zhenhua Luo

Authors
  1. Guangwei Huang
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Contributions

GWH, HLB, and WL designed and performed experiments, analyzed and interpreted data, and prepared the manuscript. PZ, ZGD, XLX, MZL, BW, HXA, and LDXL participated in the design of the study and performed the statistical analysis. HYZ and ZHL conceived of the study and participated in its design and coordination and review of this manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Haiyan Zhou, Zhenhua Luo or Wei Li.

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Conflict of interest

Author Guangwei Huang declares that he/she has no conflict of interest; author Hailong Bao declares that he/she has no conflict of interest; author Peng Zhan declares that he/she has no conflict of interest; author Xiyang Lu declares that he/she has no conflict of interest; author Zonggang Duan declares that he/she has no conflict of interest; author Xinlin Xiong declares that he/she has no conflict of interest; author Muzhi Lin declares that he/she has no conflict of interest; author Bing Wang declares that he/she has no conflict of interest; author Hongxin An declares that he/she has no conflict of interest; author Luanda Xiahou declares that he/she has no conflict of interest; author Haiyan Zhou declares that he/she has no conflict of interest; author Zhenhua Luo declares that he/she has no conflict of interest, author Wei Li declares that he/she has no conflict of interest.

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Authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Animal experiments were approved by the Animal Experimentation Committee of the Institutional Review Board of Guizhou Medical University (License No. 2019 (105)) and complied with the guidelines of Guizhou Medical University for the care and use of animals. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and the anshun city science and technology plan project.

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Huang, G., Bao, H., Zhan, P. et al. PCSK9 regulates myocardial ischemia–reperfusion injury through parkin/pink1-mediated autophagy pathway. Mol. Cell. Toxicol. 20, 367–376 (2024). https://doi.org/10.1007/s13273-023-00352-3

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