miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1

PLoS One. 2013;8(2):e56280. doi: 10.1371/journal.pone.0056280. Epub 2013 Feb 18.

Abstract

The lining of the adult heart contains epicardial mesothelial cells (EMCs) that have the potential to undergo fibrogenic Epithelial-to-Mesenchymal Transition (EMT) during cardiac injury. EMT of EMCs has therefore been suggested to contribute to the heterogeneous fibroblast pool that mediates cardiac fibrosis. However, the molecular basis of this process is poorly understood. Recently, microRNAs (miRNAs) have been shown to regulate a number of sub-cellular events in cardiac disease. Hence, we hypothesized that miRNAs regulate fibrogenic EMT in the adult heart. Indeed pro-fibrogenic stimuli, especially TGF-β, promoted EMT progression in EMC cultures, which resulted in differential expression of numerous miRNAs, especially the pleiotropic miR-21. Accordingly, ectopic expression of miR-21 substantially promoted the fibroblast-like phenotype arising from fibrogenic EMT, whereas an antagonist that targeted miR-21 blocked this effect, as assessed on the E-cadherin/α-smooth muscle actin balance, cell viability, matrix activity, and cell motility, thus making miR-21 a relevant target of EMC-derived fibrosis. Several mRNA targets of miR-21 was differentially regulated during fibrogenic EMT of EMCs and miR-21-dependent targeting of Programmed Cell Death 4 (PDCD4) and Sprouty Homolog 1 (SPRY1) significantly contributed to the development of a fibroblastoid phenotype. However, PDCD4- and SPRY1-targeting was not entirely ascribable to all phenotypic effects from miR-21, underscoring the pleiotropic biological role of miR-21 and the increasing number of recognized miR-21 targets.

Publication types

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

MeSH terms

  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Cluster Analysis
  • Epithelial-Mesenchymal Transition / genetics*
  • Fibrosis / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Myocardium
  • Pericardium / metabolism*
  • Pericardium / pathology*
  • Phenotype
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Primary Cell Culture
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • MIRN21 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • PDCD4 protein, human
  • Phosphoproteins
  • RNA-Binding Proteins
  • SPRY1 protein, human