IJBCB：TGFβ1/15-LO通路可能成为肺动脉高压新靶点

近日，国际著名杂志The International Journal of Biochemistry & Cell Biology在线刊登了哈尔滨医科大学研究人员的最新研究成果“The key role of transforming growth factor-beta receptor I and 15-lipoxygenase in hypoxia-induced proliferation of pulmonary artery smooth muscle cells，”，文章中研究者揭示了治疗肺动脉高压提供了新的治疗靶点。

该研究通过共聚焦（检测有丝分裂，蛋白共定位），免疫共沉淀（蛋白之间相互作用）， BrdU（DNA合成），流式细胞仪（细胞周期进程）等实验手段，证实了缺氧诱导15-脂氧合酶（15-LO）表达是通过转化生长因子β1（TGFβ1）通路，15-LO参与了TGFβ1介导的细胞活力，DNA合成和细胞周期进程。该研究结果显示：15-LO通路在TGFβRI介导的缺氧条件下的肺动脉平滑肌细胞增殖中扮演了重要的作用。该研究的最大创新点在于首次发现TGFβ1作为15-LO的上游通路在缺氧肺动脉高压中的作用，这一发现为治疗肺动脉高压提供了新的治疗靶点。

刘云同学2008年毕业于哈尔滨医科大学药学专业，获学士学位；现为哈尔滨医科大学2010级药理学专业博士研究生，导师为朱大岭教授。截至目前，刘云以第一作者身份发表SCI论文5篇，影响因子累计达到14.4；参与发表SCI论文5篇，影响因子累计18.6。

doi:10.1016/j.biocel.2012.04.009
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The key role of transforming growth factor-beta receptor I and 15-lipoxygenase in hypoxia-induced proliferation of pulmonary artery smooth muscle cells

Yun Liua, 1, Cui Maa, 1, Qianlong Zhanga, Lei Yua, Jun Maa, Lei Zhanga, Xuewei Haoa, Fangyuan Caoc, Lin Wangc, Daling Zhua, b, ,

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 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 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.