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

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

Author information

1
Basic Medical College, Hebei Medical University, Shijiazhuang, China.
2
Medical Research Center, Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan, China.
3
Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Department of Basic Medicine, Xiamen Medical College, Xiamen, China.
4
College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China.
5
Basic Medicine College, North China University of Science and Technology, Tangshan, China.
6
College of Preventive Medicine, North China University of Science and Technology, Tangshan, China.
7
Basic Medical College, Hebei Medical University, Shijiazhuang, China. Electronic address: fangyang@ncst.edu.cn.

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

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