Cardiomyocyte‐specific Peli1 contributes to the pressure overload‐induced cardiac fibrosis through miR ‐494‐3p‐dependent exosomal communication

Abstract Cardiac fibrosis is an essential pathological process in pressure overload (PO)‐induced heart failure. Recently, myocyte‐fibroblast communication is proven to be critical in heart failure, in which, pathological growth of cardiomyocytes (CMs) may promote fibrosis via miRNAs‐containing exosomes (Exos). Peli1 regulates the activation of NF‐κB and AP‐1, which has been demonstrated to engage in miRNA transcription in cardiomyocytes. Therefore, we hypothesized that Peli1 in CMs regulates the activation of cardiac fibroblasts (CFs) through an exosomal miRNA‐mediated paracrine mechanism, thereby promoting cardiac fibrosis. We found that CM‐conditional deletion of Peli1 improved PO‐induced cardiac fibrosis. Moreover, Exos from mechanical stretch (MS)‐induced WT CMs (WT MS‐Exos) promote activation of CFs, Peli1 −/− MS‐Exos reversed it. Furthermore, miRNA microarray and qPCR analysis showed that miR‐494‐3p was increased in WT MS‐Exos while being down regulated in Peli1 −/− MS‐Exos. Mechanistically, Peli1 promoted miR‐494‐3p expression via NF‐κB/AP‐1 in CMs, and then miR‐494‐3p induced CFs activation by inhibiting PTEN and amplifying the phosphorylation of AKT, SMAD2/3, and ERK. Collectively, our study suggests that CMs Peli1 contributes to myocardial fibrosis via CMs‐derived miR‐494‐3p‐enriched exosomes under PO, and provides a potential exosomal miRNA‐based therapy for cardiac fibrosis.