Hypoxia activates 15-PGDH and its metabolite 15-KETE to promote pulmonary artery endothelial cells proliferation via ERK1/2 signalling
Hypoxia activates 15-PGDH and its metabolite 15-KETE to promote pulmonary artery endothelial cells proliferation via ERK1/2 signalling
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DOI：
10.1111/bph.12594
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发表时间：
2014-07-01
影响因子：
7.3
通讯作者：
Zhu, Daling
中科院分区：
文献类型：
--
作者：
Ma, Cui;Liu, Yun;Zhu, Daling
背景与目的肺动脉内皮细胞的功能障碍和损伤在慢性缺氧引起的高血压中起重要作用。缺氧的一个后果是15-羟基前列腺素脱氢酶（PGDH）活性增加。在这里，我们详细探讨了缺氧对肺动脉内皮细胞增殖的影响。实验方法采用溴脱氧尿苷掺入、细胞周期分析、免疫组化、Western blot等方法研究缺氧诱导15-PGDH活性及其产物15-酮- 6z、8Z、11Z、13e -二十碳四烯酸（15-KETE）对内皮细胞增殖的影响。划伤和管形成试验也用于研究内皮细胞的迁移。关键结果15- kete增加了DNA合成，促进了缺氧时G(0)/G(1)期向S期的过渡。抑制15-PGDH或抑制15-PGDH的siRNA可逆转这些作用。15-KETE也激活ERK1/2信号通路。15- kete诱导的细胞迁移和小管形成可以通过阻断ERK1/2而不是p38 MAPK途径逆转。结论和意义缺氧诱导的内皮细胞增殖和迁移是缺氧肺血管重构的重要潜在机制，似乎是由15-PGDH和15-KETE通过ERK1/2信号通路介导的。
BACKGROUND AND PURPOSEDysfunction and injury of endothelial cells in the pulmonary artery play critical roles in the hypertension induced by chronic hypoxia. One consequence of hypoxia is increased activity of 15-hydroxyprostaglandin dehydrogenase (PGDH). Here, we have explored, in detail, the effects of hypoxia on the proliferation of pulmonary artery endothelial cells.EXPERIMENTAL APPROACHWe used bromodeoxyuridine incorporation, cell-cycle analysis, immunohistochemistry and Western blot analysis to study the effects of hypoxia, induced 15-PGDH) activity and its product, 15-keto-6Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15-KETE), on endothelial cell proliferation. Scratch-wound and tube formation assays were also used to study migration of endothelial cells.KEY RESULTS15-KETE increased DNA synthesis and enhanced the transition from the G(0)/G(1) phase to the S phase in hypoxia. Inhibition of 15-PGDH or siRNA for 15-PGDH reversed these effects. 15-KETE also activated the ERK1/2 signalling pathway. 15-KETE-induced cell migration and tube formation were reversed by blocking ERK1/2, but not the p38 MAPK pathway.CONCLUSIONS AND IMPLICATIONSHypoxia-induced endothelial proliferation and migration, an important underlying mechanism contributing to hypoxic pulmonary vascular remodelling, appears to be mediated by 15-PGDH and 15-KETE, via the ERK1/2 signalling pathway.