15-PGDH/15-KETE plays a role in hypoxia-induced pulmonary vascular remodeling through ERK1/2-dependent PAR-2 pathway.
15-PGDH/15-KETE plays a role in hypoxia-induced pulmonary vascular remodeling through ERK1/2-dependent PAR-2 pathway.
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DOI：
10.1016/j.cellsig.2014.03.008
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发表时间：
2014-07
影响因子：
4.8
通讯作者：
Liuping Wei;Xiufeng Yu;Hengyuan Shi;Bo Zhang;Mingming Lian;Jing Li;Tingting Shen;Y. Xing
中科院分区：
文献类型：
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作者：
Liuping Wei;Xiufeng Yu;Hengyuan Shi;Bo Zhang;Mingming Lian;Jing Li;Tingting Shen;Y. Xing
我们已经确定15-羟基二十碳四烯酸是调节与缺氧诱导的肺动脉高压（PH）相关的肺血管重塑（PVR）的重要因素，其进一步被15-羟基前列腺素脱氢酶（15-PGDH）代谢形成15-酮二十碳四烯酸（15-KETE）。然而，15-PGDH和15-KETE对PH的作用尚未确定。本研究的目的是研究15-PGDH/15-KETE通路是否调节PH中缺氧诱导的PVR并表征其潜在机制。采用免疫组化、超高效液相色谱、Western印迹、溴脱氧尿苷掺入和细胞周期分析等方法进行检测。我们的研究结果表明，15-PGDH的表达和内源性15-KETE的水平显着升高，在人类与PH和缺氧PH大鼠肺。低氧刺激肺动脉平滑肌细胞（PASMC）增殖，可能与15-PGDH/15-KETE比值升高有关。15-PGDH/15-KETE信号通路也能刺激细胞周期进程，促进细胞周期相关蛋白的表达。此外，15-KETE促进PASMCs的细胞周期进展和增殖依赖于蛋白酶激活受体2（PAR-2）。ERK 1/2信号可能是缺氧条件下15-PGDH/15-KETE诱导PAR-2表达所必需的。我们的研究表明，15-PGDH/15-KETE通过ERK 1/2介导的PAR-2表达刺激PASMCs的细胞周期进程和增殖，并参与低氧诱导的PVR。
We have established that 15-hydroxyeicosatetraenoic acid is an important factor in regulation of pulmonary vascular remodeling (PVR) associated with hypoxia-induced pulmonary hypertension (PH), which is further metabolized by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) to form 15-ketoeicosatetraenoic acid (15-KETE). However, the role of 15-PGDH and 15-KETE on PH has not been identified. The purpose of this study was to investigate whether 15-PGDH/15-KETE pathway regulates hypoxia-induced PVR in PH and to characterize the underlying mechanisms. To accomplish this, Immunohistochemistry, Ultra Performance Liquid Chromatography, Western blot, bromodeoxyuridine incorporation and cell cycle analysis were preformed. Our results showed that the levels of 15-PGDH expression and endogenous 15-KETE were drastically elevated in the lungs of humans with PH and hypoxic PH rats. Hypoxia stimulated pulmonary arterial smooth muscle cell (PASMC) proliferation, which seemed to be due to the increased 15-PGDH/15-KETE. 15-PGDH/15-KETE pathway was also capable of stimulating the cell cycle progression and promoting the cell cycle-related protein expression. Furthermore, 15-KETE-promoted cell cycle progression and proliferation in PASMCs depended on protease-activated receptor 2 (PAR-2). ERK1/2 signaling was likely required for 15-PGDH/15-KETE-induced PAR-2 expression under hypoxia. Our study indicates that 15-PGDH/15-KETE stimulates the cell cycle progression and proliferation of PASMCs involving ERK1/2-mediated PAR-2 expression, and contributes to hypoxia-induced PVR.