Open AccessExtracellular vesicle‐packaged mitochondrial disturbing miRNA exacerbates cardiac injury during acute myocardial infarction
Author(s) -
Sun Ping,
Wang Chao,
Mang Ge,
Xu Xiangli,
Fu Shuai,
Chen Jianfeng,
Wang Xiaoqi,
Wang Weiwei,
Li Hairu,
Zhao Peng,
Li Yifei,
Chen Qi,
Wang Naixin,
Tong Zhonghua,
Fu Xin,
Lang Ying,
Duan Shasha,
Liu Dongmei,
Zhang Maomao,
Tian Jiawei
Publication year - 2022
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.779
Subject(s) - sirt3 , mitochondrial biogenesis , myocardial infarction , microbiology and biotechnology , medicine , sirtuin , extracellular vesicle , sirtuin 1 , mitochondrion , microrna , cardioprotection , cancer research , microvesicles , downregulation and upregulation , biology , acetylation , biochemistry , gene
Mounting evidence suggests that extracellular vesicles (EVs) are effective communicators in biological signalling in cardiac physiology and pathology. 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)‐induced EVs can impair cardiomyocyte survival and exacerbate cardiac injury. EV‐encapsulated miR‐503, which is enriched during the early phase of AMI, is a critical molecule that mediates myocardial injury. Functional studies revealed that miR‐503 promoted cardiomyocyte death by directly binding to peroxisome proliferator‐activated receptor gamma coactivator‐1β (PGC‐1β) 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‐503 in EVs after AMI. Hypoxia induced rapid H3K4 methylation of the promoter of the methyltransferase‐like 3 gene ( METTL3 ) and resulted in its overexpression. METTL3 overexpression evokes N6‐methyladenosine (m 6 A)‐dependent miR‐503 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‐secreted miR‐503 shuttling.