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The effects of bosentan on thrombin‐activated fibroblasts and endothelial cells
Author(s) -
Bogatkevich Galina S,
LudwickaBradley Anna,
Silver Richard M
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.774.3
Subject(s) - bosentan , fibroblast , myofibroblast , angiogenesis , endothelial stem cell , thrombin , endothelin 1 , cancer research , endothelin receptor , microbiology and biotechnology , medicine , chemistry , immunology , fibrosis , endocrinology , biology , receptor , in vitro , biochemistry , platelet
Endothelin‐1 and thrombin are elevated during lung injury and repair, as seen in scleroderma and other interstitial lung diseases, and each plays important roles in remodeling epithelium, blood vessels and connective tissue. Both factors promote myofibroblast differentiation, the hallmark of pulmonary fibrosis. Here we show that thrombin significantly induces endothelin‐1 expression in human lung fibroblasts. Bosentan, the dual, specific and competitive inhibitor of endothelin, significantly decreases α‐SMA, collagen gel contraction, and proliferation of human lung fibroblasts stimulated by thrombin, suggesting that thrombin‐induced differentiation of fibroblasts to the myofibroblast phenotype is at least in part regulated by endothelin‐1. Moreover, bosentan inhibits the basal level of fibroblast proliferation suggesting that endogenous endothelin may be in part responsible for fibroblast proliferation. The effect of bosentan on endothelial cells is concentration dependent. At concentrations of 10μM and 100μM bosentan inhibits thrombin‐induced endothelial cell migration and angiogenesis, whereas low‐dose (10nM) bosentan demonstrates a significant angiogenic effect. Bosentan rapidly phosphorylates Akt in endothelial cells and promotes cell survival. Our results demonstrate that low‐dose bosentan protects endothelial cells from apoptosis and increases their functionality. We conclude that bosentan may be a promising therapeutic agent in the treatment of microvascular injury as seen in scleroderma and other interstitial lung diseases. Study sponsor: Actelion Pharmaceuticals