A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes

J Mol Cell Cardiol. 2018 Jan;114:72-82. doi: 10.1016/j.yjmcc.2017.11.003. Epub 2017 Nov 7.

Abstract

Background: Cardiac injury is accompanied by dynamic changes in the expression of microRNAs (miRs), small non-coding RNAs that post-transcriptionally regulate target genes. MiR-125b-5p is downregulated in patients with end-stage dilated and ischemic cardiomyopathy, and has been proposed as a biomarker of heart failure. We previously reported that the β-blocker carvedilol promotes cardioprotection via β-arrestin-biased agonism of β1-adrenergic receptor while stimulating miR-125b-5p processing in the mouse heart. We hypothesize that β1-adrenergic receptor/β-arrestin1-responsive miR-125b-5p confers the improvement of cardiac function and structure after acute myocardial infarction.

Methods and results: Using cultured cardiomyocyte (CM) and in vivo approaches, we show that miR-125b-5p is an ischemic stress-responsive protector against CM apoptosis. CMs lacking miR-125b-5p exhibit increased susceptibility to stress-induced apoptosis, while CMs overexpressing miR-125b-5p have increased phospho-AKT pro-survival signaling. Moreover, we demonstrate that loss-of-function of miR-125b-5p in the mouse heart causes abnormalities in cardiac structure and function after acute myocardial infarction. Mechanistically, the improvement of cardiac function and structure elicited by miR-125b-5p is in part attributed to repression of the pro-apoptotic genes Bak1 and Klf13 in CMs.

Conclusions: In conclusion, these findings reveal a pivotal role for miR-125b-5p in regulating CM survival during acute myocardial infarction.

Keywords: Apoptotic genes; Biased G protein-coupled receptor signaling; Cardioprotection; MicroRNAs; β-arrestin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Cardiotonic Agents / metabolism
  • Carvedilol / pharmacology*
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Gene Knockdown Techniques
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Biological
  • Myocardial Infarction / genetics*
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Rats, Sprague-Dawley
  • Repressor Proteins / metabolism*
  • Ventricular Dysfunction, Left / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism*

Substances

  • Cardiotonic Agents
  • Cell Cycle Proteins
  • KLF13 protein, rat
  • Klf13 protein, mouse
  • Kruppel-Like Transcription Factors
  • MIRN125 microRNA, rat
  • MicroRNAs
  • Mirn125 microRNA, mouse
  • Repressor Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • Carvedilol