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Rac inhibition reverses the phenotype of fibrotic fibroblasts

Shi-Wen , Xu and Liu, Shangxi and Eastwood, Mark and Sonnylal, Sonali and Denton, Christopher P. and Abraham, David J. and Leask, Andrew (2009) Rac inhibition reverses the phenotype of fibrotic fibroblasts. PLoS ONE, 4 (10). e7438. ISSN 1932-6203

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Official URL: http://dx.doi.org/10.1371/journal.pone.0007438

Abstract

Background Fibrosis, the excessive deposition of scar tissue by fibroblasts, is one of the largest groups of diseases for which there is no therapy. Fibroblasts from lesional areas of scleroderma patients possess elevated abilities to contract matrix and produce α−smooth muscle actin (α-SMA), type I collagen and CCN2 (connective tissue growth factor, CTGF). The basis for this phenomenon is poorly understood, and is a necessary prerequisite for developing novel, rational anti-fibrotic strategies. Methods and Findings Compared to healthy skin fibroblasts, dermal fibroblasts cultured from lesional areas of scleroderma (SSc) patients possess elevated Rac activity. NSC23766, a Rac inhibitor, suppressed the persistent fibrotic phenotype of lesional SSc fibroblasts. NSC23766 caused a decrease in migration on and contraction of matrix, and α−SMA, type I collagen and CCN2 mRNA and protein expression. SSc fibroblasts possessed elevated Akt phosphorylation, which was also blocked by NSC23766. Overexpression of rac1 in normal fibroblasts induced matrix contraction and α−SMA, type I collagen and CCN2 mRNA and protein expression. Rac1 activity was blocked by PI3kinase/Akt inhibition. Basal fibroblast activity was not affected by NSC23766. Conclusion Rac inhibition may be considered as a novel treatment for the fibrosis observed in SSc.

Item Type:Article
Research Community:University of Westminster > Life Sciences, School of
ID Code:11269
Deposited On:23 Oct 2012 14:09
Last Modified:23 Oct 2012 14:09

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