title: Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK.
abstract: 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.
authors.affiliation: Centre for Rheumatology, Department of Medicine, Royal Free and University College London, United Kingdom.
authors.forename: Shi-wen
authors.initials: SW
authors.lastname: Xu
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Howat
authors.forename: Elisabetta A
authors.initials: EA
authors.lastname: Renzoni
authors.forename: Alan
authors.initials: A
authors.lastname: Holmes
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Pearson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Dashwood
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: Roland M
authors.initials: RM
authors.lastname: du Bois
authors.forename: Carol M
authors.initials: CM
authors.lastname: Black
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
authors.forename: David J
authors.initials: DJ
authors.lastname: Abraham
mesh_terms: D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D019332:Endothelin-1; D016326:Extracellular Matrix Proteins; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human