title: The key role of transforming growth factor-beta receptor I and 15-lipoxygenase in hypoxia-induced proliferation of pulmonary artery smooth muscle cells.
abstract: Our laboratory has proved that 15-hydroxyeicosatetraenoic acid, a product of arachidonic acid catalyzed by 15-lipoxygenase (15-LO), plays a pivotal role in hypoxic pulmonary arterial hypertension. However, the mechanisms of how hypoxia regulates 15-LO expression are still unclear. As the formation of endogenous transforming growth factor-beta1 (TGF-β1), implicated in pulmonary arterial hypertension pathogenesis, was promoted by hypoxia, we suspect whether hypoxia-induced the expression of 15-LO is via the TGF-β1 pathway. We found that treatment of pulmonary artery smooth muscle cells with TGF-β1 significantly increased the expression of 15-LO and levels of 15-hydroxyeicosatetraenoic acid, product of 15-LO, which were inhibited by transforming growth factor-beta receptor I (TGFβRI) inhibitor, SD-208 and siRNA targeted to knockdown rat TGFβRI. Moreover, our results showed that TGF-β1 regulated the cell cycle progression and made more cells from the G(0)/G(1) phase to the G(2)/M+S phase and enhanced the microtubule formation in cell nucleus. Additionally, we found that the 15-LO pathway was involved in TGFβ-1-mediated cell viability, DNA synthesis and the cell cycle progression. Our data provide novel evidence that hypoxia induced 15-LO expression is through TGF-β1, and 15-LO pathway plays a critical role in TGFβRI mediated the proliferation of pulmonary artery smooth muscle cells induced by hypoxia. Thus, new strategies aimed at combined blockade of TGFβRI as well as 15-LO may yield optimal therapeutic benefits.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University-Daqing, Daqing 163319, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Cui
authors.initials: C
authors.lastname: Ma
authors.forename: Qianlong
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Xuewei
authors.initials: X
authors.lastname: Hao
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Cao
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D001093:Arachidonate 15-Lipoxygenase; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat