Exosomal miR-218-5p/miR-363-3p from Endothelial Progenitor Cells Ameliorate Myocardial Infarction by Targeting the p53/JMY Signaling Pathway

Accumulating evidence has shown that endothelial progenitor cell-derived exosomes (EPC-Exos) can ameliorate myocardial fibrosis. The purpose of the present study was to investigate the effects of EPC-Exos-derived microRNAs (miRNAs) on myocardial infarction (MI). A miRNA-Seq dataset of miRNAs differentially expressed between EPCs and exosomes was collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the miRNA expression indicated by miRNA-Seq. Immunofluorescence, cell proliferation, and angiogenesis assays were employed to investigate the effects of miRNAs on cardiac fibroblasts (CFs) in vitro . Interactions between miRNAs and their respective targets were examined via immunoblotting, qRT-PCR, and luciferase reporter assays. An MI rat model was constructed, and various staining and immunohistochemical assays were performed to explore the mechanisms underlying the miRNA-mediated effects on MI. miR-363-3p and miR-218-5p were enriched in EPC-Exos, and miR-218-5p and miR-363-3p mimic or inhibitor enhanced or suppressed CF proliferation and angiogenesis, respectively. miR-218-5p and miR-363-3p regulated p53 and junction-mediating and regulatory protein (JMY) by binding to the promoter region of p53 and the 3′ untranslated region of JMY. Additionally, treatment of CFs with Exo-miR-218-5p or Exo-miR-363-3p upregulated p53 and downregulated JMY expression, promoted mesenchymal-endothelial transition, and inhibited myocardial fibrosis. Administration of exosomes containing miR-218-5p mimic or miR-363-3p mimic ameliorated left coronary artery ligation-induced MI and restored myocardial tissue integrity in the MI model rats. In summary, these results show that the protective ability of EPC-Exos against MI was mediated by the shuttled miR-218-5p or miR-363-3p via targeting of the p53/JMY signaling pathway.