Department of Biopharmaceutical Sciences, College of Pharmacy, Nangang District, Harbin Medical University, Harbin, China.
Prostaglandins Leukot Essent Fatty Acids. 2012 Jan-Feb;86(1-2):85-90. doi: 10.1016/j.plefa.2011.10.001. Epub 2011 Oct 22.
The initial event of hypoxic pulmonary hypertension is acute hypoxic pulmonary vasoconstriction followed by remodeling of pulmonary arteries. Although 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE] is found to be able to induce hypoxic pulmonary vasoconstriction, role of 15(S)-HETE in pulmonary artery smooth muscle cells (PASMCs) proliferation has been studied less. We sought evidence for a role of 15(S)-HETE in the development of hypoxia-induced pulmonary hypertension. We found that hypoxia enhances 15-lipoxygenase-2 (15-LOX-2) expression and stimulates cultured rabbit PASMCs proliferation. 15(S)-HETE at concentration 0.1 μM stimulated proliferation of PASMCs and induced ERK 1/ERK 2 phosphorylation but had no effect on p38 kinase expression as assessed by Western blotting. 15(S)-HETE-stimulated PASMC proliferation was blocked by the MEK inhibitors PD-98059. Hypoxia (3% O(2))-stimulated PASMC proliferation was blocked by U0126, a MEK inhibitor, as well as by NDGA and CDC, inhibitors of 15-LOX, but not by the p38 MAPK inhibitor SB-202190. We conclude that 15-LOX-2 and its product, 15(S)-HETE, are important intermediates in hypoxia-induced rabbit PASMC proliferation and may participate in hypoxia-induced pulmonary hypertension.
低氧性肺动脉高压的初始事件是急性低氧性肺血管收缩，随后是肺血管重塑。虽然 15(S)-羟基二十碳四烯酸[15(S)-HETE]被发现能够诱导低氧性肺血管收缩，但 15(S)-HETE 在肺动脉平滑肌细胞（PASMCs）增殖中的作用研究较少。我们寻求 15(S)-HETE 在低氧诱导性肺动脉高压发展中的作用证据。我们发现，低氧增强 15-脂氧合酶-2（15-LOX-2）的表达并刺激培养的兔 PASMCs 增殖。浓度为 0.1μM 的 15(S)-HETE 刺激 PASMCs 增殖并诱导 ERK 1/ERK 2 磷酸化，但对 Western blot 评估的 p38 激酶表达没有影响。MEK 抑制剂 PD-98059 阻断 15(S)-HETE 刺激的 PASMC 增殖。MEK 抑制剂 U0126 以及 15-LOX 的抑制剂 NDGA 和 CDC 阻断低氧（3%O2）刺激的 PASMC 增殖，但 p38 MAPK 抑制剂 SB-202190 则没有。我们的结论是，15-LOX-2 及其产物 15(S)-HETE 是低氧诱导兔 PASMC 增殖的重要中间产物，可能参与低氧诱导性肺动脉高压。
