Modulation of miR-10a-mediated TGF-β1/Smads signaling affects atrial fibrillation-induced cardiac fibrosis and cardiac fibroblast proliferation

Biosci Rep. 2019 Feb 8;39(2):BSR20181931. doi: 10.1042/BSR20181931. Print 2019 Feb 28.

Abstract

Atrial fibrillation (AF) rat models and rat cardiac fibroblasts (CFs) with overexpressed or inhibited miR-10a were used to investigate the possible role of miR-10a-mediated transforming growth factor-β (TGF-β1)/Smads signaling in cardiac fibrosis and fibroblast proliferation in rats with AF. Gene ontology and pathway enrichment analyses were used to identify the possible function of miR-10a in cardiac fibrosis. The results showed that overexpressed miR-10a significantly prolonged the duration of AF, further elevated the collagen volume fraction (CVF), and increased the viability of CFs in AF rats; these findings were in contrast with the findings for rats with inhibition of miR-10a (all P<0.05). Moreover, miR-10a overexpression could promote miR-10a, collagen-I, collagen III, α-SMA, and TGF-β1 protein expression and increase the levels of hydroxyproline but reduced Smad7 protein expression in atrial tissues and CFs in AF rats. Not surprisingly, inhibiting miR-10a led to completely contrasting results (all P<0.05). Moreover, TGF-β1 treatment could reverse the inhibitory effect of miR-10a down-regulation on cardiac fibrosis in CFs. Bioinformatics analysis and luciferase reporter assay results demonstrated that miR-10a bound directly to the 3'-UTR of BCL6, which is involved in cell growth and proliferation. Thus, our study indicate that down-regulation of miR-10a may inhibit collagen formation, reduce atrial structure remodeling, and decrease proliferation of CFs, eventually suppressing cardiac fibrosis in AF rats via inhibition of the TGF-β1/Smads signaling pathway.

Keywords: Atrial fibrillation; Cardiac fibrosis; MiR-10a; Proliferation; TGF-β1/Smads.

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / pathology*
  • Cell Proliferation / drug effects
  • Collagen / genetics
  • Collagen / metabolism
  • Disease Models, Animal
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Gene Expression Regulation
  • Hydroxyproline / metabolism
  • Male
  • MicroRNAs / metabolism*
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • Proto-Oncogene Proteins c-bcl-6 / metabolism
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Smad Proteins / genetics*
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta1 / metabolism*
  • Transforming Growth Factor beta1 / pharmacology

Substances

  • 3' Untranslated Regions
  • MIRN10 microRNA, rat
  • MicroRNAs
  • Proto-Oncogene Proteins c-bcl-6
  • Smad Proteins
  • Transforming Growth Factor beta1
  • Collagen
  • Hydroxyproline