Endothelin receptor antagonists: effects on extracellular matrix synthesis in primary cultures of skin fibroblasts from systemic sclerosis patients.

Abstract

Endothelin-1 (ET-1) seems to enhance the pro-fibrotic protein synthesis by skin fibroblasts and its effects are mediated by endothelin-A and B (ETA and ETB) receptors. This study aimed to investigate the effects of ETA and ETB receptor antagonists (ETARA-sitaxsentan and ETA/BRA-bosentan) on type I collagen (COL-1), fibronectin (FN) and fibrillin-1 (FBL-1) synthesis in primary cultures of skin fibroblasts from systemic sclerosis patients. Primary cultures of fibroblasts were obtained from skin biopsies of 6 female systemic sclerosis patients and were treated with ET-1 (100 nM) for 24 and 48 hrs with or without pre-treatment (1 hr) with ETARA (2 μM) or ETA/BRA (10 μM). Primary culture of human scleroderma skin fibroblasts not treated with ET-1 or ET receptor antagonists (ETARA and ETA/BRA) were used as controls. COL-1, FN and FBL-1 synthesis was evaluated by immunocytochemistry and Western blot analysis. Immunocytochemistry and Western blot analysis showed that ET-1 significantly increased COL-1 and FN synthesis at 24 and 48 hrs and FBL-1 synthesis at 48 hrs vs untreated cells. ETARA significantly contrasted the ET-1-mediated increase in COL-1 and FN at 24 hrs as well as COL-1 and FBL-1 at 48 hrs, but not FN synthesis vs ET-1-treated fibroblasts. Conversely, ETA/BRA significantly antagonized the ET-1-mediated overproduction of COL-1 and FN both at 24 and 48 hrs and the FBL-1 synthesis at 48 hrs vs ET-1-treated cells. The single ETARA treatment seems to contrast significantly the increase in COL-1 synthesis, whereas the dual ETA/BRA treatment seems active in significantly antagonizing both COL-1 and FN overproduction induced by ET-1. In conclusion, ET-1 antagonism might have positive effects in contrasting the profibrotic activity of systemic sclerosis skin fibroblasts.

• Authors: S Soldano, P Montagna, R Brizzolara, C Ferrone, A Parodio, A Sulli, B Seriolo, B Villaggio, M Cutolo
• Journal: Reumatismo (Reumatismo) Vol. 64 Issue 5 Pg. 326-34 (Dec 11 2012) ISSN: 0048-7449 [Print] Italy
• PMID: 23256109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type I
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Extracellular Matrix Proteins
• FBN1 protein, human
• Fibrillin-1
• Fibrillins
• Fibronectins
• Isoxazoles
• Microfilament Proteins
• Sulfonamides
• Thiophenes
• sitaxsentan
• Bosentan

Topics

• Aged
• Bosentan
• Cells, Cultured
• Collagen Type I (biosynthesis)
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Extracellular Matrix Proteins (biosynthesis)
• Female
• Fibrillin-1
• Fibrillins
• Fibroblasts (drug effects, metabolism)
• Fibronectins (biosynthesis)
• Fibrosis
• Humans
• Isoxazoles (pharmacology)
• Microfilament Proteins (biosynthesis)
• Middle Aged
• Primary Cell Culture
• Scleroderma, Systemic (metabolism, pathology)
• Sulfonamides (pharmacology)
• Thiophenes (pharmacology)