miR-1 exacerbates cardiac ischemia-reperfusion injury in mouse models

PLoS One. 2012;7(11):e50515. doi: 10.1371/journal.pone.0050515. Epub 2012 Nov 30.

Abstract

Recent studies have revealed the critical role of microRNAs (miRNAs) in regulating cardiac injury. Among them, the cardiac enriched microRNA-1(miR-1) has been extensively investigated and proven to be detrimental to cardiac myocytes. However, solid in vivo evidence for the role of miR-1 in cardiac injury is still missing and the potential therapeutic advantages of systemic knockdown of miR-1 expression remained unexplored. In this study, miR-1 transgenic (miR-1 Tg) mice and locked nucleic acid modified oligonucleotide against miR-1 (LNA-antimiR-1) were used to explore the effects of miR-1 on cardiac ischemia/reperfusion injury (30 min ischemia followed by 24 h reperfusion). The cardiac miR-1 level was significantly increased in miR-1 Tg mice, and suppressed in LNA-antimiR-1 treated mice. When subjected to ischemia/reperfusion injury, miR-1 overexpression exacerbated cardiac injury, manifested by increased LDH, CK levels, caspase-3 expression, apoptosis and cardiac infarct area. On the contrary, LNA-antimiR-1 treatment significantly attenuated cardiac ischemia/reperfusion injury. The expression of PKCε and HSP60 was significantly repressed by miR-1 and enhanced by miR-1 knockdown, which may be a molecular mechanism for the role miR-1 in cardiac injury. Moreover, luciferase assay confirmed the direct regulation of miR-1 on protein kinase C epsilon (PKCε) and heat shock protein 60 (HSP60). In summary, this study demonstrated that miR-1 is a causal factor for cardiac injury and systemic LNA-antimiR-1 therapy is effective in ameliorating the problem.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Base Sequence
  • Caspase 3 / metabolism
  • Chaperonin 60 / genetics
  • Chaperonin 60 / metabolism
  • Creatine Kinase / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Myocardial Infarction / complications
  • Myocardial Ischemia / complications*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oligonucleotides / genetics
  • Protein Kinase C-epsilon / genetics
  • Protein Kinase C-epsilon / metabolism
  • Reperfusion Injury / complications*
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology

Substances

  • Chaperonin 60
  • MicroRNAs
  • Mirn1 microRNA, mouse
  • Oligonucleotides
  • locked nucleic acid
  • L-Lactate Dehydrogenase
  • Protein Kinase C-epsilon
  • Creatine Kinase
  • Caspase 3

Grant support

This work was supported by National Natural Science Foundation of China (81130088, 30971252, 81000100, 81170219), the Funds for Creative Research Groups of The National Natural Science Foundation of China (81121003), China Postdoctoral Science Foundation (20080440915), and Heilongjiang Province Science Foundation for Youths(QC07C69). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.