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

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Abstract
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.
Funding Information
  • Natural Science Foundation of Guangdong Province (2021A1515010178, 2018A030313771, 2018A030313782, 2019A1515010329)
  • National Natural Science Foundation of China (81700263)
  • Guangzhou Municipal Science and Technology Program key projects (201604020129)

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