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However, the role of EVs in cardiac injury, particularly in ischemic myocardial scenarios, has not been fully elucidated. Here, we report that acute myocardial infarction (AMI)\u2010induced EVs can impair cardiomyocyte survival and exacerbate cardiac injury. EV\u2010encapsulated miR\u2010503, which is enriched during the early phase of AMI, is a critical molecule that mediates myocardial injury. Functional studies revealed that miR\u2010503 promoted cardiomyocyte death by directly binding to peroxisome proliferator\u2010activated receptor gamma coactivator\u20101\u03b2 (PGC\u20101\u03b2) and a mitochondrial deacetylase, sirtuin 3 (SIRT3), thereby triggering mitochondrial metabolic dysfunction and cardiomyocyte death. Mechanistically, we identified endothelial cells as the primary source of miR\u2010503 in EVs after AMI. Hypoxia induced rapid H3K4 methylation of the promoter of the <jats:italic>methyltransferase\u2010like 3<\/jats:italic> gene (<jats:italic>METTL3<\/jats:italic>) and resulted in its overexpression. METTL3 overexpression evokes N6\u2010methyladenosine (m<jats:sup>6<\/jats:sup>A)\u2010dependent miR\u2010503 biogenesis in endothelial cells. In summary, this study highlights a novel endogenous mechanism wherein EVs aggravate myocardial injury during the onset of AMI via endothelial cell\u2010secreted miR\u2010503 shuttling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.779","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T13:14:21Z","timestamp":1650633261000},"source":"Crossref","is-referenced-by-count":33,"title":["Extracellular vesicle\u2010packaged mitochondrial disturbing miRNA exacerbates cardiac injury during acute myocardial infarction"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6674-8714","authenticated-orcid":false,"given":"Ping","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Ultrasound The Second Affiliated Hospital of Harbin Medical University  Harbin China"},{"name":"The Key Laboratory of Myocardial Ischemia Harbin Medical University, Ministry of Education  Harbin 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