MicroRNA-214 Mediates Isoproterenol-induced Proliferation and Collagen Synthesis in Cardiac Fibroblasts

Sci Rep. 2015 Dec 22;5:18351. doi: 10.1038/srep18351.

Abstract

The action of β-adrenergic receptors (β-ARs) induces cardiac fibroblast (CF) proliferation and collagen synthesis and is a major source of the cardiac fibrosis caused by various diseases. Recently, microRNA-214 (miR-214) was found to play an important role in the pathogenesis of cardiac remodelling. In the present study, we examined the role and the underlying mechanism of miR-214 in isoproterenol (ISO, a β-AR agonist)-induced CF proliferation and collagen synthesis. The expression of miR-214 was increased in both ISO-mediated fibrotic heart tissue and fibroblasts. Downregulation of miR-214 by antagonists attenuated the proliferation and collagen synthesis in ISO-treated CFs. Using bioinformatics analysis and luciferase assays, mitofusin2 (Mfn2), a critical regulator of cell proliferation and tissue fibrosis, was identified as a direct target gene of miR-214; this result was confirmed by western blot analysis. Additionally, corresponding to the upregulation of miR-214, the expression of Mfn2 was downregulated in the fibrotic heart and fibroblasts. Furthermore, the downregulation of miR-214 inhibited the activation of ERK1/2 MAPK signalling induced by ISO treatment. In conclusion, our study demonstrated that miR-214 mediates CF proliferation and collagen synthesis via inhibition of Mfn2 and activation of ERK1/2 MAPK signalling, which provides a new explanation for the mechanism of β-AR activation-induced cardiac fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Proliferation / drug effects
  • Collagen / biosynthesis*
  • Conserved Sequence / genetics
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibrosis
  • GTP Phosphohydrolases
  • Gene Knockdown Techniques
  • Isoproterenol / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Membrane Proteins / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Mitochondrial Proteins / metabolism
  • Molecular Sequence Data
  • Myocardium / pathology*
  • Phosphorylation / drug effects
  • Rats, Sprague-Dawley
  • Transfection
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • 3' Untranslated Regions
  • Membrane Proteins
  • MicroRNAs
  • Mirn214 microRNA,rat
  • Mitochondrial Proteins
  • Collagen
  • Extracellular Signal-Regulated MAP Kinases
  • GTP Phosphohydrolases
  • Mfn2 protein, rat
  • Isoproterenol