Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK.

Journal article

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: Xu, S; Howat, S; Renzoni, E; Holmes, A; Pearson, J

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 279
• Issue: 22
• Pages: 23098-23103
• Publication date: 2004-05-01
• DOI: 10.1074/jbc.m400516200
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Signal Transduction; Extracellular Matrix; Humans; Gene Expression Regulation; Lung; MAP Kinase Kinase Kinase 1; Extracellular Matrix Proteins; MAP Kinase Kinase Kinases; Mitogen-Activated Protein Kinases; Endothelin-1; Fibroblasts