title: SB-431542, a specific inhibitor of the TGF-β type I receptor inhibits hypoxia-induced proliferation of pulmonary artery adventitial fibroblasts.
abstract: The vascular remodeling process plays an important role in the pathology of hypoxia-induced pulmonary hypertension, and it includes cell proliferation, cell motility, cell synthesis and collagen coagulation. Due to their proliferation and synthesis ability, the adventitial fibroblasts are thought to be critical in the vascular remodeling process initiated in response to hypoxia. However, the factors driving hypoxia-induced fibroblast proliferation and synthesis have yet to be elucidated, and the treatment regimens to treat hypoxia remain ineffective. As forthis study, its purpose was to examine the effects exerted by SB-431542, a small-molecule antagonist of transforming growth factor-β-receptor, on the proliferation, synthesis and collagen coagulation in cultured adventitial fibroblasts. Another aim of this study was to assess the inhibitory ability of SB-431542 on pulmonary vascular remodeling in chronic hypoxia in vivo.The cell morphology and proliferation of cultured adventitial fibroblasts was assessed by laser confocal microscopy and the MTT assay, respectively. Additionally, collagen synthesis was determined by hydroxyproline chromatography, while the expression of cytokines in adventitial fibroblasts and lung tissues was evaluated by immunohistochemical and reverse transcription PCR analyses. The results indicated that the exposure of cultured fibroblasts to 1% oxygen led to the up regulation of cell proliferation, cell synthesis. In addition, increased expression of cytokines and collagen was detected in vivo in the pulmonary artery adventitia of rats exposed to chronic hypoxia. Conversely, SB-431542 inhibited fibroblast proliferation and synthesis in the process of hypoxia-induced pulmonary hypertension (P < 0.01). Thus, the results suggested that by reducing cell proliferation, cell synthesis of vascular adventitia, small molecule inhibitors of the TGF-β1 receptors may offer a novel therapy for pulmonary hypertension.
authors.forename: Wendan
authors.initials: W
authors.lastname: Yuan
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Hongjing
authors.initials: H
authors.lastname: Cai
authors.forename: Xuhong
authors.initials: X
authors.lastname: Sun
authors.forename: Dongxia
authors.initials: D
authors.lastname: Yang
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.forename: Changzhu
authors.initials: C
authors.lastname: Jin
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004149:Dioxoles / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects*; D006909:Hydroxyproline / Q000378:metabolism; D000860:Hypoxia / Q000473:pathology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011651:Pulmonary Artery / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C541116:ACTA2 protein, human; D000199:Actins; D001549:Benzamides; D016207:Cytokines; D004149:Dioxoles; D016328:NF-kappa B; D018125:Receptors, Transforming Growth Factor beta; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D006909:Hydroxyproline