LncRNA 2810403D21Rik/Mirf promotes ischemic myocardial injury by regulating autophagy through targeting Mir26a

Autophagy. 2020 Jun;16(6):1077-1091. doi: 10.1080/15548627.2019.1659610. Epub 2019 Sep 12.

Abstract

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.

Keywords: Autophagy; Mir26a; Usp15; lncRNA-2810403D21Rik/Mirf; myocardial infarction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagosomes / drug effects
  • Autophagosomes / genetics
  • Autophagosomes / metabolism*
  • Autophagosomes / ultrastructure
  • Autophagy / drug effects
  • Autophagy / genetics*
  • Cell Survival / drug effects
  • Gene Knockdown Techniques
  • Gene Silencing
  • HEK293 Cells
  • Humans
  • Hydrogen Peroxide / toxicity
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microscopy, Electron, Transmission
  • Mutation
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Ubiquitin-Specific Proteases / genetics
  • Ubiquitin-Specific Proteases / metabolism
  • Up-Regulation

Substances

  • MicroRNAs
  • Mirn26 microRNA, mouse
  • RNA, Long Noncoding
  • Hydrogen Peroxide
  • Ubiquitin-Specific Proteases
  • Usp15 protein, mouse

Grants and funding

This study was supported by the National Natural Science Foundation of China (81770284, 31671187, 81673425).