Chan Zhang, Hao Hao, Nan Mu, Yishi Wang, Yin Yue, Lu Yu, Heng Ma
Apoptotic vesicles (ApoVs) facilitate intercellular communication. Cardiac fibroblasts (CFbs) undergo apoptosis during myocardial ischemia-reperfusion (MI/R), but their ApoVs' role in cardiomyocyte survival is unknown. Here, CFbs-ApoVs were isolated from fibroblast conditioned medium (FCM). Transmission electron microscopy, nanoparticle tracking analysis, and protein blotting were used to characterize the properties of CFbs-ApoVs. Bioinformatics screening and experimental validation identified the molecular markers of CFbs-ApoVs. Enriched CFbs-ApoVs were explored in their effects and mechanisms on cardiomyocytes in vitro and in vivo. This study identified and characterized the apoptotic CFbs-derived ApoVs subtypes: CD22+-CFbs-ApoVs. The results showed that CD22+-CFbs-ApoVs were efficiently homed to cardiomyocytes. Mechanistically, miR-1246, which is enriched in CD22+-CFbs-ApoVs, effectively inhibits p53 protein expression and the translocation of p53 from the nucleus to mitochondria in MI/R-injured cardiomyocytes, rescues mitochondrial damage, and suppresses cardiomyocyte apoptosis. Overexpression of miR-1246 or inhibition of p53 enhanced the protective effect of CD22+-CFbs-ApoVs on injured cardiomyocytes. We found that CD22+-CFbs-ApoVs are effective endogenous cardioprotective vectors that can target cardiomyocytes for fusion, and we also revealed the dual inhibitory effect on p53 mediated by miR-1246. This study revealed a previously unidentified cell-to-cell communication mechanism of apoptotic CFbs that serves to promote cardiomyocyte survival during MI/R, and it also implies the potential use of ApoVs for combating MI/R injury.