Abstract
Endothelin-1 (ET-1) acts as a key regulator of vasoconstriction and fibrosis. Many previous studies have focused on the role of ET-1 in scleroderma (systemic sclerosis, SSc). We investigated the effects of ET-1 on the production of extracellular matrix in SSc and normal skin fibroblasts. Primary cultured dermal fibroblasts from SSc patients and healthy controls were treated with ET-1 (25 ng/mL) for 0 min, 15 min, 1 h, 24 h, 48 h and 72 h, respectively. Our results showed that, in SSc fibroblasts, ET-1 upregulated collagen type I, connective tissue growth factor (CTGF), type I plasminogen activator inhibitor (PAI-1) and pAkt in a time-dependent manner within 72 h; in normal fibroblasts, 25 ng/mL ET-1 stimulation correlated with high levels of CTGF, PAI-1 and pAkt. The secretion of fibronectin (FN), collagen type I, and PAI-1 is markedly increased in the supernatant of both SSc fibroblasts and normal fibroblasts. Furthermore, ET-1 phosphorylates Smad2 and Smad3 in normal fibroblasts, but not in SSc fibroblasts. In conclusion, our results demonstrated that ET-1 may induce fibrosis in dermal fibroblasts through Akt signals.
Keywords:
Akt; endothelin-1; fibroblast; smad; systemic sclerosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Case-Control Studies
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Collagen Type I / genetics
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Collagen Type I / metabolism
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Connective Tissue Growth Factor / genetics
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Connective Tissue Growth Factor / metabolism
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Endothelin-1 / metabolism
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Endothelin-1 / pharmacology*
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Female
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Fibroblasts / drug effects*
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Fibronectins / biosynthesis
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Fibronectins / metabolism
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Fibrosis
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Gene Expression Regulation
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Humans
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Male
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Middle Aged
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Phosphorylation
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Plasminogen Activator Inhibitor 1 / genetics
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Plasminogen Activator Inhibitor 1 / metabolism
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Primary Cell Culture
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Proto-Oncogene Proteins c-akt / genetics*
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Proto-Oncogene Proteins c-akt / metabolism
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Scleroderma, Systemic / genetics*
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Scleroderma, Systemic / metabolism
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Scleroderma, Systemic / pathology
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Signal Transduction
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Skin / drug effects*
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Skin / metabolism
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Skin / pathology
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Smad2 Protein / genetics
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Smad2 Protein / metabolism
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
Substances
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CCN2 protein, human
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Collagen Type I
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Endothelin-1
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Fibronectins
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Plasminogen Activator Inhibitor 1
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Recombinant Proteins
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SERPINE1 protein, human
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SMAD2 protein, human
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SMAD3 protein, human
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Smad2 Protein
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Smad3 Protein
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Connective Tissue Growth Factor
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Proto-Oncogene Proteins c-akt