Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation
Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation
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DOI：
10.1152/ajplung.00114.2005
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发表时间：
2006-02-01
影响因子：
4.9
通讯作者：
Fanburg, BL
中科院分区：
文献类型：
--
作者：
Preston, IR;Hill, NS;Fanburg, BL
花生四烯酸代谢的12-脂氧合酶（12- lo）途径刺激各种癌细胞的生长和转移，而12- lo的代谢物12(S)-羟基二十碳四烯酸[12(S)-HETE]促进主动脉平滑肌细胞（SMCs）的增殖。然而，12-LO对肺血管的影响尚未被研究过。我们寻找证据证明12- lo和12(S)-HETE在缺氧诱导的肺动脉高压发展中的作用。我们发现慢性缺氧大鼠肺匀浆中12-LO基因和蛋白表达升高。12-LO抗体免疫组化染色显示，大肺动脉内皮细胞、中小肺动脉SMCs（可能还有内皮细胞）和缺氧肺肺泡壁强烈染色。缺氧培养大鼠肺动脉SMCs中12-LO蛋白表达升高。浓度低至10(-5)μ M的12(S)-HETE刺激了肺动脉SMCs的增殖。Western blotting检测显示，12(S)-HETE诱导erk1 / erk2磷酸化，但对p38激酶表达无影响。MEK抑制剂PD-98059可阻断12(S)- hete刺激的SMC增殖，而p38 MAPK抑制剂SB-202190则不能。缺氧（3%）刺激的肺动脉SMC增殖被U0126 （MEK抑制剂）和黄芩素（12-LO抑制剂）阻断。我们认为，12- lo及其产物12(S)-HETE是缺氧诱导的肺动脉SMC增殖的重要中间体，并可能参与缺氧诱导的肺动脉高压。
The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and metastasis of various cancer cells and the 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], enhances proliferation of aortic smooth muscle cells (SMCs). However, pulmonary vascular effects of 12-LO have not been previously studied. We sought evidence for a role of 12-LO and 12(S)-HETE in the development of hypoxia-induced pulmonary hypertension. We found that 12-LO gene and protein expression is elevated in lung homogenates of rats exposed to chronic hypoxia. Immunohistochemical staining with a 12-LO antibody revealed intense staining in endothelial cells of large pulmonary arteries, SMCs (and possibly endothelial cells) of medium and small-size pulmonary arteries and in alveolar walls of hypoxic lungs. 12-LO protein expression was increased in hypoxic cultured rat pulmonary artery SMCs. 12(S)-HETE at concentrations as low as 10(-5) mu M stimulated proliferation of pulmonary artery SMCs. 12(S)-HETE induced ERK 1/ERK 2 phosphorylation but had no effect on p38 kinase expression as assessed by Western blotting. 12(S)-HETE-stimulated SMC proliferation was blocked by the MEK inhibitor PD-98059, but not by the p38 MAPK inhibitor SB-202190. Hypoxia (3%)-stimulated pulmonary artery SMC proliferation was blocked by both U0126, a MEK inhibitor, and baicalein, an inhibitor of 12-LO. We conclude that 12-LO and its product, 12(S)-HETE, are important intermediates in hypoxia-induced pulmonary artery SMC proliferation and may participate in hypoxia-induced pulmonary hypertension.