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ERK1/2通路参与15--羟二十碳四烯酸收缩缺氧大鼠肺动脉的过程

吕昌莲, 叶宏, 唐晓波, 朱大岭

哈尔滨医科大学药学院.黑龙江,哈尔滨 150086；哈尔滨医科大学附属二院药学部.黑龙江,哈尔滨 150086；黑龙江省生物医药工程重点实验室省部共建国家重点实验培育基地.黑龙江,哈尔滨 150086

摘要

缺氧诱导的15--羟二十碳四烯酸(15--hydroxyeicosatetraenoic acid, 15--HETE)是引起肺动脉收缩的重要介导因子。15--HETE引起肺动脉收缩的信号转导途径尚不清楚。该研究旨在确定细胞外信号调节激酶1/2 (extracellular signal--regulated kinase--1/2, ERK1/2)信号转导通路是否参与15--HETE收缩缺氧大鼠肺动脉的过程。采用组织浴槽肺动脉环张力检测、蛋白质免疫印迹 (Western blot)和免疫细胞化学方法。制备缺氧大鼠动物模型，成年雄性Wistar大鼠在低氧环境下(吸入氧分数为0.12)正常喂养 9 d。显微分离直径1---1.5 mm肺动脉，剪成长为3 mm的动脉环，进行血管张力检测。用ERK1/2上游激酶(MEK)抑制剂PD98059 抑制ERK1/2活性。结果显示，PD98059可明显抑制15--HETE对缺氧大鼠肺动脉环的收缩作用。在去除内皮的肺动脉环， PD98059仍可明显降低15--HETE的缩血管作用。Western blot和免疫细胞化学结果都显示，15--HETE 能促进ERK1/2磷酸化。由此表明ERK1/2信号转导通路参与15--HETE收缩缺氧大鼠肺动脉的过程。

关键词： 缺氧; 15-羟二十碳四烯酸; 15-脂氧化酶; 细胞外信号调节激酶

ERK1/2 signaling pathway is involved in 15--hydroxyeicosatetraenoic acid--induced hypoxic pulmonary vosoconstriction

Lu Changlian, Ye Hong, Tang Xiaobo, Zhu Daling

College of Pharmacy, Harbin Medical University.Harbin 150086,Heilongjiang；China；Key Laboratory of Biopharmaceutical Engineering of Heilongjiang Province.Harbin 150086,Heilongjiang

Abstract

Hypoxia-induced 15-hydroxyeicosatetraenoic acid (15-HETE) is an essential mediator to constrict pulmonary arteries (PA). The signaling pathway involved in 15-HETE-induced PA vasoconstriction remains obscure. The aim of the present study was to test the hypothesis that hypoxic PA constriction induced by 15-HETE was possibly regulated by the extracellular signal-regulated kinase-1/2 (ERK1/2) pathway. PA ring tension measurement, Western blot and immunocytochemistry were used in the study to determine the possible role of ERK1/2 in 15-HETE-induced PA vasoconstriction. The organ bath for PA rings tension study was employed. Adult male Wistar rats were raised in hypoxic environment with fractional inspired oxygen (FIO_(2), 0.12) for 9 d. PA 1--1.5 mm in diameter were dissected and cut into 3 mm long rings for tension study. ERK1/2 up-stream kinase (MEK) inhibitor PD98059, which blocks the activation of ERK1/2, was used. The results showed that pretreatment of PD98059 significantly blunted 15-HETE-induced PA vasoconstrictions in the rings from hypoxic rat. Moreover, in endothelium-denuded rings, PD98059 also significantly attenuated 15-HETE-induced vasoconstriction. Phosphorylation of ERK1/2 in pulmonary arterial smooth muscle cells (PASMCs) of rat was enhanced evidently when stimulated by 15-HETE. Thus, the data suggest that ERK1/2 signaling pathway is involved in 15-HETE-induced hypoxic pulmonary vasoconstriction.

Key words: Hypoxia;15-hydroxyeicosatetraenoic acid;15-lipoxygenase;extracellular signal-regulated kinase

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引用本文：

吕昌莲, 叶宏, 唐晓波, 朱大岭. ERK1/2通路参与15--羟二十碳四烯酸收缩缺氧大鼠肺动脉的过程 [J]. 生理学报 2005; 57 (5): .

Lu Changlian, Ye Hong, Tang Xiaobo, Zhu Daling. ERK1/2 signaling pathway is involved in 15--hydroxyeicosatetraenoic acid--induced hypoxic pulmonary vosoconstriction . Acta Physiol Sin 2005; 57 (5): (in Chinese with English abstract).