The key role of transforming growth factor-beta receptor I and 15-lipoxygenase in hypoxia-induced proliferation of pulmonary artery smooth muscle cells

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• 作者：Yun Liu^a ; ¹ ; Cui Ma^a ; ¹ ; Qianlong Zhang^a ; Lei Yu^a ; Jun Ma^a ; Lei Zhang^a ; Xuewei Hao^a ; Fangyuan Cao^c ; Lin Wang^c ; Daling Zhu^a ; ^b ; ^{dalingz@yahoo.com}
• 关键词：PAH ; pulmonary arterial hypertension ; 15-LO ; 15-lipoxygenase ; 15-HETE ; 15-hydroxyeicosatetraenoic acid ; TGF-尾1 ; transforming growth factor-beta1 ; TGF尾RI ; transforming growth factor-beta receptor I ; PASMCs ; pulmonary artery smooth muscle cells ; CDC ; cinn
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2012
• 期刊代码：127_13572725
• 类别：med
• 出版时间：July, 2012
• 卷：44
• 期：7
• 页码：1184-1202
• 文件大小：3843 K

摘要

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-尾1), implicated in pulmonary arterial hypertension pathogenesis, was promoted by hypoxia, we suspect whether hypoxia-induced the expression of 15-LO is via the TGF-尾1 pathway. We found that treatment of pulmonary artery smooth muscle cells with TGF-尾1 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 (TGF尾RI) inhibitor, SD-208 and siRNA targeted to knockdown rat TGF尾RI. Moreover, our results showed that TGF-尾1 regulated the cell cycle progression and made more cells from the G₀/G₁ phase to the G₂/M + S phase and enhanced the microtubule formation in cell nucleus. Additionally, we found that the 15-LO pathway was involved in TGF尾-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-尾1, and 15-LO pathway plays a critical role in TGF尾RI mediated the proliferation of pulmonary artery smooth muscle cells induced by hypoxia. Thus, new strategies aimed at combined blockade of TGF尾RI as well as 15-LO may yield optimal therapeutic benefits.