Crucial role of extracellular signal-regulated kinase pathway in reactive oxygen species-mediated endothelin-1 gene expression induced by endothelin-1 in rat cardiac fibroblasts

Cheng Ming Cheng, Hong Jye Hong, Ju Chi Liu, Neng Lang Shih, Shu Hui Juan, Shih Hurng Loh, Paul Chan, Jin Jer Chen, Tzu-Hurng Cheng

研究成果: 雜誌貢獻文章

66 引文 斯高帕斯(Scopus)

摘要

Endothelin-1 (ET-1) has been implicated in fibroblast proliferation. However, the mechanism involving ET-1 is not clear., The present study was performed to examine the role of endogenous ET-1 in ET-1 - stimulated fibroblast proliferation and to investigate the regulatory mechanism of ET-1 - induced ET-1 gene expression in cardiac fibroblasts. Both ETA receptor antagonist [(hexahydro-1 H-azepinyl)carbonyl-Leu-D-Trp-D-OH (BQ485)] and endothelin-converting enzyme inhibitor (phosphoramidon) inhibited the increased DNA synthesis caused by ET-1. ET-1 gene was induced by ET-1, as revealed with Northern blotting and ET-1 promoter activity assay. ET-1 increased intracellular reactive oxygen species (ROS), which were significantly inhibited by BQ485 and antioxidants. Antioxidants suppressed ET-1 gene expression and DNA synthesis stimulated by ET-1. ET-1 activated mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase, which were significantly inhibited by antioxidants. Only ERK inhibitor U0126 could inhibit ET-1 - induced transcription of the ET-1 gene. Cotransfection of dominant-negative mutant of Ras, Raf, and MEK1 decreased the ET-1 - induced increase in ET-1 transcription, suggesting that the Ras-Raf-ERK pathway is required for ET-1 action. Truncation and mutational analysis of the ET-1 gene promoter showed that the activator protein-1 (AP-1) binding site was an important cis-element in ET-1 - induced ET-1 gene expression. Antioxidants attenuated the ET-1 - stimulated AP-1 binding activity. Our data suggest that ROS were involved in ET-1 - induced fibroblast proliferation and mediated ET-1induced activation of ERK pathways, which culminated in ET-1 gene expression.
原文英語
頁(從 - 到)1002-1011
頁數10
期刊Molecular Pharmacology
63
發行號5
DOIs
出版狀態已發佈 - 五月 1 2003

ASJC Scopus subject areas

  • Pharmacology

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