M2 Macrophages-Derived Small Extracellular Vesicles Carry miR-142-5p to Mitigate Myocardial Injury in Acute Myocardial Infarction by Regulating the RBMS1/TFRC Axis

Abstract —M2 macrophage-derived small extracellular vesicles (M2 sEVs) have been shown to alleviate myocardial cell injury and cardiac dysfunction in mice with acute myocardial infarction (AMI); however, the underlying mechanisms remain to be fully elucidated. In this study, we observed that miR-142-5p was overexpressed in M2 sEVs. To investigate its functional role, an AMI mouse model was established by ligation of the left anterior descending coronary artery, followed by intramyocardial injection of M2 sEVs carrying a miR-142-5p antagomir. Our results demonstrated that M2 sEVs promoted cardiac function recovery, ameliorated pathological changes in myocardial tissue, and reduced cardiomyocyte apoptosis in AMI mice through the delivery of miR-142-5p. Furthermore, an in vitro injury model was established by exposing mouse cardiomyocytes to hypoxia/reoxygenation (H/R). Treatment with M2 sEVs or a miR-142-5p mimic effectively attenuated H/R-induced ferroptosis and restored cardiomyocyte proliferation. Mechanistically, miR-142-5p directly targeted and negatively regulated RBMS1 expression. As an RNA-binding protein, RBMS1 bound to the 3'UTR region of TFRC, thereby enhancing TFRC mRNA stability. By downregulating RBMS1, miR-142-5p promoted TFRC degradation and subsequently suppressed ferroptosis, ultimately alleviating cardiac dysfunction in AMI mice. Consistent with these findings, in vivo inhibition of ferroptosis using ferrostatin-1 also ameliorated cardiac dysfunction in AMI mice. Collectively, our study reveals that M2 macrophage-derived sEVs deliver miR-142-5p, which suppresses cardiomyocyte ferroptosis by targeting the RBMS1/TFRC axis, thereby promoting cardiac functional recovery following AMI.