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Effects of macitentan and its active metabolite on cultured human systemic sclerosis and control skin fibroblasts

(2015) JOURNAL OF RHEUMATOLOGY. 42(3). p.456-463
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Abstract
Objective. To investigate the effects of the endothelin 1 (ET-1) receptor antagonists (ETRA) macitentan, its active metabolite ACT-132577, and bosentan on myofibroblast activation and extracellular matrix production induced by ET-1 in cultured systemic sclerosis (SSc) and control skin fibroblasts. Methods. Fibroblasts were obtained from skin biopsies of 6 patients with SSc and 5 healthy subjects. Some cultured cells were untreated or treated with macitentan, ACT-132577, or bosentan alone (10 mu M). Other cultured cells were treated with ET-1 alone (100 nM) or with ETRA, and after 1 h, also with ET-1. After 48 h of treatment, myofibroblast activation was investigated to evaluate the alpha-smooth muscle actin (alpha-SMA) expression by immunofluorescence; type I collagen (COL-1) and fibronectin (FN) were investigated by immunocytochemistry, Western blotting, and quantitative real-time PCR (qRT-PCR). Statistical analysis was performed by the nonparametric Mann-Whitney U test. Results. In cultured SSc skin fibroblasts, only the treatment with macitentan significantly reduced the basal level of alpha-SMA expression (p = 0.03 vs untreated cells). Macitentan also significantly reduced the basal level of COL-1 synthesis, similarly to bosentan (p < 0.05 vs untreated cells). Macitentan or ACT-132577 antagonized the ability of ET-1 to further induce alpha-SMA expression (p = 0.03), COL-1, and FN synthesis (p = 0.03, p = 0.005); bosentan showed similar effects. These results obtained by immunofluorescence and immunocytochemistry were confirmed by Western blotting and qRT-PCR. The downregulatory effects exerted by ETRA were observed also in cultured human control skin fibroblasts. Conclusion. Macitentan and ACT-132577 seem to downregulate in vitro the profibrotic myofibroblast phenotype induced by ET-1 in cultured human SSc skin fibroblasts.
Keywords
SKIN FIBROSIS, ENDOTHELIN RECEPTOR ANTAGONISTS, ENDOTHELIN 1, SYSTEMIC SCLEROSIS, EXTRACELLULAR MATRIX, HUMAN SKIN FIBROBLASTS, ENDOTHELIN RECEPTOR ANTAGONIST, MYOFIBROBLAST, FIBROSIS, EXPRESSION, PHARMACOKINETICS, CONTRIBUTES, MECHANISMS, BOSENTAN, TRIAL, DISEASES

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MLA
Cutolo, Maurizio et al. “Effects of Macitentan and Its Active Metabolite on Cultured Human Systemic Sclerosis and Control Skin Fibroblasts.” JOURNAL OF RHEUMATOLOGY 42.3 (2015): 456–463. Print.
APA
Cutolo, M., Montagna, P., Brizzolara, R., Smith, V., Alessandri, E., Villaggio, B., Sulli, A., et al. (2015). Effects of macitentan and its active metabolite on cultured human systemic sclerosis and control skin fibroblasts. JOURNAL OF RHEUMATOLOGY, 42(3), 456–463.
Chicago author-date
Cutolo, Maurizio, Paola Montagna, Renata Brizzolara, Vanessa Smith, Elisa Alessandri, Barbara Villaggio, Alberto Sulli, Pietro Paolo Tavilla, Carmen Pizzorni, and Stefano Soldano. 2015. “Effects of Macitentan and Its Active Metabolite on Cultured Human Systemic Sclerosis and Control Skin Fibroblasts.” Journal of Rheumatology 42 (3): 456–463.
Chicago author-date (all authors)
Cutolo, Maurizio, Paola Montagna, Renata Brizzolara, Vanessa Smith, Elisa Alessandri, Barbara Villaggio, Alberto Sulli, Pietro Paolo Tavilla, Carmen Pizzorni, and Stefano Soldano. 2015. “Effects of Macitentan and Its Active Metabolite on Cultured Human Systemic Sclerosis and Control Skin Fibroblasts.” Journal of Rheumatology 42 (3): 456–463.
Vancouver
1.
Cutolo M, Montagna P, Brizzolara R, Smith V, Alessandri E, Villaggio B, et al. Effects of macitentan and its active metabolite on cultured human systemic sclerosis and control skin fibroblasts. JOURNAL OF RHEUMATOLOGY. 2015;42(3):456–63.
IEEE
[1]
M. Cutolo et al., “Effects of macitentan and its active metabolite on cultured human systemic sclerosis and control skin fibroblasts,” JOURNAL OF RHEUMATOLOGY, vol. 42, no. 3, pp. 456–463, 2015.
@article{7061511,
  abstract     = {Objective. To investigate the effects of the endothelin 1 (ET-1) receptor antagonists (ETRA) macitentan, its active metabolite ACT-132577, and bosentan on myofibroblast activation and extracellular matrix production induced by ET-1 in cultured systemic sclerosis (SSc) and control skin fibroblasts. 
Methods. Fibroblasts were obtained from skin biopsies of 6 patients with SSc and 5 healthy subjects. Some cultured cells were untreated or treated with macitentan, ACT-132577, or bosentan alone (10 mu M). Other cultured cells were treated with ET-1 alone (100 nM) or with ETRA, and after 1 h, also with ET-1. After 48 h of treatment, myofibroblast activation was investigated to evaluate the alpha-smooth muscle actin (alpha-SMA) expression by immunofluorescence; type I collagen (COL-1) and fibronectin (FN) were investigated by immunocytochemistry, Western blotting, and quantitative real-time PCR (qRT-PCR). Statistical analysis was performed by the nonparametric Mann-Whitney U test. 
Results. In cultured SSc skin fibroblasts, only the treatment with macitentan significantly reduced the basal level of alpha-SMA expression (p = 0.03 vs untreated cells). Macitentan also significantly reduced the basal level of COL-1 synthesis, similarly to bosentan (p < 0.05 vs untreated cells). Macitentan or ACT-132577 antagonized the ability of ET-1 to further induce alpha-SMA expression (p = 0.03), COL-1, and FN synthesis (p = 0.03, p = 0.005); bosentan showed similar effects. These results obtained by immunofluorescence and immunocytochemistry were confirmed by Western blotting and qRT-PCR. The downregulatory effects exerted by ETRA were observed also in cultured human control skin fibroblasts. 
Conclusion. Macitentan and ACT-132577 seem to downregulate in vitro the profibrotic myofibroblast phenotype induced by ET-1 in cultured human SSc skin fibroblasts.},
  author       = {Cutolo, Maurizio and Montagna, Paola and Brizzolara, Renata and Smith, Vanessa and Alessandri, Elisa and Villaggio, Barbara and Sulli, Alberto and Tavilla, Pietro Paolo and Pizzorni, Carmen and Soldano, Stefano},
  issn         = {0315-162X},
  journal      = {JOURNAL OF RHEUMATOLOGY},
  keywords     = {SKIN FIBROSIS,ENDOTHELIN RECEPTOR ANTAGONISTS,ENDOTHELIN 1,SYSTEMIC SCLEROSIS,EXTRACELLULAR MATRIX,HUMAN SKIN FIBROBLASTS,ENDOTHELIN RECEPTOR ANTAGONIST,MYOFIBROBLAST,FIBROSIS,EXPRESSION,PHARMACOKINETICS,CONTRIBUTES,MECHANISMS,BOSENTAN,TRIAL,DISEASES},
  language     = {eng},
  number       = {3},
  pages        = {456--463},
  title        = {Effects of macitentan and its active metabolite on cultured human systemic sclerosis and control skin fibroblasts},
  url          = {http://dx.doi.org/10.3899/jrheum.141070},
  volume       = {42},
  year         = {2015},
}

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