Autophagy · 2019
LncRNA 2810403D21Rik/Mirf promotes ischemic myocardial injury by regulating autophagy through targeting Mir26a.
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Liang Haihai, Su Xiaomin, Wu Qiuxia, Shan Huitong, Lv Lifang, Yu Tong, Zhao Xiaoguang, Sun Jian, Yang Rui, Zhang Lu, Yan He, Zhou Yuhong, Li Xuelian, Du Zhimin, Shan Hongli
Аннотация
UNLABELLED: More evidence is emerging of the roles long non-coding RNAs (lncRNAs) play as regulatory factors in a variety of biological processes, but the mechanisms underlying the function of lncRNAs in acute myocardial infarction (AMI) have not been explicitly delineated. The present study identified the lncRNA 2810403D21Rik/AK007586/Mirf (myocardial infarction-regulatory factor), that inhibited macroautophagy/autophagy by modulating Mir26a (microRNA 26a). Inhibition of Mir26a led to cardiac injury both in vitro and in vivo, whereas overexpression of Mir26a attenuated ischemic stress-induced cell death by activating autophagy through targeting Usp15 (ubiquitin specific peptidase 15). More importantly, 2810403D21Rik/Mirf acted as a competitive endogenous RNA (ceRNA) of Mir26a; forced expression of 2810403D21Rik/Mirf downregulated Mir26a to inhibit autophagy. In contrast, loss of 2810403D21Rik/Mirf resulted in upregulation of Mir26a to promote autophagy and alleviate cardiac injury, which in turn improved cardiac function in MI mice. This study identified a lncRNA 2810403D21Rik/Mirf that functions as an anti-autophagic molecule via ceRNA activity toward Mir26a. Our findings suggest that knockdown of 2810403D21Rik/Mirf might be a novel therapeutic approach for cardiac diseases associated with autophagy.
ABBREVIATIONS: 3-MA: 3-methyladenine; AAV-9: adenovirus associated virus-9; agoMir26a: cholesterol-conjugated Mir26a mimic; AMI: acute myocardial infarction; AMO-26a: Mir26a inhibitor; ATG: autophagy related; BECN1: beclin 1; ceRNA: competitive endogenous RNAs; EF: ejection fraction; f-2810403D21Rik/Mirf: fragment encompassing the Mir26a binding site; FS: fraction shortening; GFP-mRFP: a plasmid expressing green fluorescent protein-monomeric red fluorescent protein; lncRNA: long non-coding RNA; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; Mirf: myocardial infarction-regulatory factor; miRNAs: microRNAs; NC: negative control; NMCMs: neonatal mice cardiomyocytes; shRNA: short hairpin RNA; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Usp15: ubiquitin specific peptidase 15.
ABBREVIATIONS: 3-MA: 3-methyladenine; AAV-9: adenovirus associated virus-9; agoMir26a: cholesterol-conjugated Mir26a mimic; AMI: acute myocardial infarction; AMO-26a: Mir26a inhibitor; ATG: autophagy related; BECN1: beclin 1; ceRNA: competitive endogenous RNAs; EF: ejection fraction; f-2810403D21Rik/Mirf: fragment encompassing the Mir26a binding site; FS: fraction shortening; GFP-mRFP: a plasmid expressing green fluorescent protein-monomeric red fluorescent protein; lncRNA: long non-coding RNA; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; Mirf: myocardial infarction-regulatory factor; miRNAs: microRNAs; NC: negative control; NMCMs: neonatal mice cardiomyocytes; shRNA: short hairpin RNA; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Usp15: ubiquitin specific peptidase 15.