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.
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 ET(A) receptor antagonist [(hexahydro-1H-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-1- induced activation of ERK pathways, which culminated in ET-1 gene expression.[1]References
- 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, C.M., Hong, H.J., Liu, J.C., Shih, N.L., Juan, S.H., Loh, S.H., Chan, P., Chen, J.J., Cheng, T.H. Mol. Pharmacol. (2003) [Pubmed]
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