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Originally published as MBC in Press, 10.1091/mbc.E03-12-0902 on March 26, 2004

Vol. 15, Issue 6, 2707-2719, June 2004

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Endothelin-1 Promotes Myofibroblast Induction through the ETA Receptor via a rac/Phosphoinositide 3-Kinase/Akt-dependent Pathway and Is Essential for the Enhanced Contractile Phenotype of Fibrotic Fibroblasts

Xu Shi-Wen *, Yunliang Chen *, Christopher P. Denton *, Mark Eastwood {dagger}, Elisabetta A. Renzoni {ddagger}, George Bou-Gharios §, Jeremy D. Pearson ||, Michael Dashwood ¶, Roland M. du Bois {ddagger}, Carol M. Black *, Andrew Leask * #, and David J Abraham *

* Centre for Rheumatology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom; {dagger} Centre for Tissue Engineering Research, University of Westminster, London W1W 6UM, United Kingdom; {ddagger} Interstitial Lung Disease Unit, Royal Brompton Hospital, Imperial College School of Medicine, London SW3 6LR, United Kingdom; § Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom; || Centre for Cardiovascular Biology and Medicine, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London SE1 1UL, United Kingdom; and Department of Molecular Pathology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom

Submitted December 17, 2003; Revised March 9, 2004; Accepted March 16, 2004
Monitoring Editor: Richard Assoian

The endothelins are a family of endothelium-derived peptides that possess a variety of functions, including vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and promotes myofibroblast contraction and migration, hence contributing to matrix remodeling during tissue repair. Here, we show that addition of ET-1 to normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including {alpha}-smooth muscle actin ({alpha}-SMA), ezrin, moesin, and paxillin. We confirm that ET-1 enhances the ability of lung fibroblasts to contract extracellular matrix, a function essential for tissue repair, through induction of de novo protein synthesis. Blockade of the Akt/phosphoinositide 3-kinase (PI3-kinase) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce {alpha}-SMA, ezrin, paxillin, and moesin and to promote matrix contraction. Dominant negative rac and Akt blocked the ability of ET-1 to promote formation of {alpha}-SMA stress fibers. Using specific ET-1 receptor inhibitors, we show that ET-1 induces collagen matrix contraction through the ETA, but not the ETB, receptor. Relative to normal pulmonary fibroblasts, fibroblasts cultured from scars of patients with the fibrotic disease systemic sclerosis (scleroderma) show enhanced ET-1 expression and binding. Systemic sclerosis lung fibroblasts show increased ability to contract a collagen matrix and elevated expression of the procontractile proteins {alpha}-SMA, ezrin, paxillin, and moesin, which are greatly reduced by antagonizing endogenous ET-1 signaling. Thus, blocking ET-1 or the PI3-kinase/Akt cascades might be beneficial in reducing scar formation in pulmonary fibrosis.

Article published online ahead of print. Mol. Biol. Cell 10.1091/mbc.E03-12-0902. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E03-12-0902.

# Corresponding author. E-mail address: a.leask{at}rfc.ucl.ac.uk.




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