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Vol. 63, Issue 5, 1002-1011, May 2003
Department of Obstetrics and Gynecology, Changhua Christian
Hospital, Changhua, Taiwan (C.-M.C.); School of Chinese Medicine, China
Medical College, Taichung, Taiwan (H.-J.H.); Department of Medicine,
Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan (J.-C.L.,
S.-H.J., P.C., T.-H.C.); Institute of Biomedical Sciences, Academia
Sinica, Taipei, Taiwan (N.-L.S., J.-J.C., T.-H.C.); and Department of
Pharmacology, National Defense Medical Center, Taipei, Taiwan (S.-H.L.,
T.-H.C.)
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-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.
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