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.
Highlights
Myocardial ischemia/reperfusion (MI/R) injury is a well-known pathological incident, which can lead to acute myocardial infarction, heart failure and even sudden cardiac death (SCD) [1]
The present study aimed to explore whether cardiac fibroblasts (CFs) derived exosomes protect cardiomyocytes against MI/R injury through suppressing cardiomyocyte pyroptosis, and to further investigate the potential molecular mechanisms in MI/R-induced injury in order to provide a novel approach for effective treatment of MI/R injury
MI/R injury is a life-threatening event that can lead to acute myocardial infarction, heart failure and SCD
Summary
Myocardial ischemia/reperfusion (MI/R) injury is a well-known pathological incident, which can lead to acute myocardial infarction, heart failure and even sudden cardiac death (SCD) [1]. It has become clear that cardiomyocyte death has determinant roles in both MI/R injury, heart failure and SCD [7]. Pyroptosis is a form of programmed necrosis but different from other programmed cell deaths, is found to be extensively implicated in MI/R injury [8]. The activation of caspase-1 cleaves gasdermin D (GSDMD) to generate N-terminal fragment oligomers in the cell membrane, which leads to pyroptotic cell death through the formation of large pore [9, 10]. Detailed elucidation of the molecular events underlying cardiomyocyte pyroptosis in MI/R injury to guide therapeutic intervention deserves exploration
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