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.