Cardiac fibroblasts secrete exosome microRNA to suppress cardiomyocyte pyroptosis in myocardial ischemia/reperfusion injury

Abstract

Molecular mechanisms underlying myocardial ischemia/reperfusion (MI/R) injury and effective strategies to treat MI/R injury are both in shortage. Although pyroptosis of cardiomyocytes and the protective role of cardiac fibroblasts (CFs) have been well recognized as targets to reduce MI/R injury and sudden cardiac death (SCD), the connection has not yet been established. Here, we showed that CFs protected cardiomyocytes against MI/R-induced injury through suppression of pyroptosis. A novel molecular mechanism underpinning this effect was further identified. Under hypoxia/reoxygenation condition, CFs were found to secrete exosomes, which contain increased level of microRNA-133a (miR-133a). These exosomes then delivered miR-133a into cardiomyocytes to target ELAVL1 and repressed cardiomyocyte pyroptosis. Based on this finding, we successfully developed a new strategy that used exosomes derived from CFs with overexpressed miR-133a to enhance the therapeutic outcomes for the MI/R injury. Overall, our results provide a novel molecular basis for understanding and treating MI/R injury, and our study also provides novel insight for the postmortem diagnosis of MI/R injury induced SCD by using exosome biomarker in forensic.