Rho GDP dissociation inhibitor α silencing attenuates silicosis by inhibiting RhoA/Rho kinase signalling

Exp Cell Res. 2019 Jul 15;380(2):131-140. doi: 10.1016/j.yexcr.2019.04.026. Epub 2019 Apr 25.

Abstract

Transforming growth factor-β1 (TGF-β1) alters the fibroblast phenotype by promoting transdifferentiation into myofibroblasts, which exhibit the ability to promote collagen synthesis and extracellular matrix (ECM) deposition, thereby playing a significant role in the pathology of silicosis. In this study, we investigated the regulatory mechanisms involved in myofibroblast transdifferentiation. Two-dimensional gel electrophoresis showed that Rho GDP-dissociation inhibitor α (RhoGDIα) was upregulated following myofibroblast transdifferentiation stimulated by TGF-β1. We hypothesised that RhoGDIα may induce myofibroblast transdifferentiation and thus result in silicosis. Accordingly, the biological significance of RhoGDIα in cell proliferation and apoptosis was investigated by deletion of RhoGDIα in MRC-5 cells. In addition, a mechanistic study showed that fasudil, an inhibitor of the RhoA/Rho kinase (ROCK) signalling pathway, reduced the levels of RhoGDIα, RhoA, and phospho-myosin phosphatase （phospho-MYPT） in MRC-5 cells and silicosis model rats. Knockdown of RhoGDIα inhibited myofibroblast transdifferentiation and collagen deposition through RhoGDIα/RhoA/ROCK signalling in silicosis model mice. Overall, downregulation of RhoGDIα may significantly promote cell apoptosis and inhibit cell growth, resulting in reversal of myofibroblast transdifferentiation by RhoA/ROCK in vitro and in vivo. These data will facilitate further exploration of the potential use of RhoGDIα as a target for silicosis therapy.

Keywords: Myofibroblast; Rho GDP dissociation inhibitor α; Silicosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Silicosis / drug therapy*
  • Silicosis / metabolism
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / metabolism*
  • rho-Associated Kinases / antagonists & inhibitors*
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / antagonists & inhibitors*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • rho Guanine Nucleotide Dissociation Inhibitor alpha
  • RHOA protein, human
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein