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J. Biol. Chem., Vol. 279, Issue 22, 23098-23103, May 28, 2004

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Endothelin-1 Induces Expression of Matrix-associated Genes in Lung Fibroblasts through MEK/ERK^*

Xu Shi-wen, Sarah L. Howat, Elisabetta A. Renzoni¶, Alan Holmes, Jeremy D. Pearson, Michael R. Dashwood||, George Bou-Gharios**, Christopher P. Denton, Roland M. du Bois¶, Carol M. Black, Andrew Leask, and David J. Abraham

From the Centre for Rheumatology, Department of Medicine and the ^||Department of Molecular Pathology, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom, the Centre for Cardiovascular Biology and Medicine, Guy's, King's, and St. Thomas' School of Biomedical Sciences, King's College London, Guy's Campus, London, SE1 1UL, United Kingdom, the ^¶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, Du Cane Road, London W12 0NN, United Kingdom

The endothelins are a family of endothelium-derived peptides that possess a variety of biological activities, including potent vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and pulmonary fibrosis. Here, we use genome-wide expression array analysis to show that the addition of ET-1 (100 nM, 4 h) to normal lung fibroblasts directly induces expression of matrix and matrix-associated genes, including the profibrotic protein CCN2 (connective tissue growth factor, or CTGF). ET-1 induces the MEK/ERK MAP kinase pathway in fibroblasts. Blockade of the MEK/ERK kinase pathway with U0126 abrogates the ability of ET-1 to induce expression of matrix and matrix-associated mRNAs and the CCN2 protein. The CCN2 promoter possesses an ET-1 response element, which maps to the previously identified basal control element-1 (BCE-1) site. Our results suggest that ET-1 induces a program of matrix synthesis in lung fibroblasts and that ET-1 may play a key role in connective tissue deposition during wound repair and in pulmonary fibrosis.

Received for publication, October 17, 2003 , and in revised form, March 22, 2004.

The Gene Expression Omnibus(GEO) series number for the expression data of this work is GSE1081.

^* This work was supported by the Raynaud's and Scleroderma Association Trust, the Scleroderma Foundation, the Wellcome Trust, the Arthritis Research Campaign, the Nightingale Trust, the Welton Foundation, and the British Heart Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 207-794-0500 ext. 4053; Fax: 207-794-0432; E-mail: a.leask{at}rfc.ucl.ac.uk.

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