PCSK9 inhibitor protects against myocardial ischemia-reperfusion injury via inhibiting LRP8/GPX4-mediated ferroptosis.

Abstract

Myocardial ischemia-reperfusion injury is accompanied by ferroptosis mediated by reactive oxygen species and iron ions, which aggravates myocardial tissue damage. The present study aims to explore the molecular mechanism underlying the mitigating effects f PCSK9 on myocardial ischemia-reperfusion injury. MI/R rat model and OGD/R induced H9c2 model were established. The interaction between PCSK9 inhibitor and LRP8 was predicted by STRING database and verified by Immunoprecipitation assay experiment. CCK-8 kit results confirmed that PCSK9 inhibitor effectively protected against cardiomyocyte damage induced by OGD/R. TTC and histological examination via H&E staining revealed a significant alleviation of myocardial infarction and pathological alterations upon treatment with the PCSK9 inhibitor. Besides, DCFH-DA staining and biochemical kit results showed that PCSK9 inhibitor could regulate the changes of ferroptosis related indicators [ROS, iron level, MDA, SOD] and inhibit ferroptosis. Rescue experiments showed that PCSK9 inhibitors targeted LRP8 expression and inhibited GPX4/ROS-mediated ferroptosis in I/R-induced rats. Our study suggested that PCSK9 inhibitors could attenuate myocardial I/R injury, with the underlying mechanism intimately tied to the targeted modulation of LRP8/GPX4-mediated ferroptosis.