Hypoxia promotes rabbit pulmonary artery smooth muscle cells proliferation through a 15-LOX-2 product 15(S)-hydroxyeicosatetraenoic acid

• Published in: Prostaglandins, leukotrienes and essential fatty acids leukotrienes and essential fatty acids, 2012-01, Vol.86 (1), p.85-90
• Main Authors: Shan, Ruihui, Chen, Li, Li, Xinyu, Wu, Hong, Liang, Qingcheng, Tang, Xiaobo
• Format: Article
• Language: English
• Subjects: 15(S)-hydroxyeicosatetraenoic acid; Advanced Basic Science; Animals; Animals, Newborn; Arachidonate 15-Lipoxygenase - metabolism; Biological and medical sciences; Blotting, Western; Butadienes - pharmacology; Caffeic Acids - pharmacology; Cell Proliferation; Cell Survival - drug effects; Cells, Cultured; Endocrinology & Metabolism; Extracellular signal-regulated kinase-1/extracellular signal-regulated kinase-2; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Hydroxyeicosatetraenoic Acids - metabolism; Hydroxyeicosatetraenoic Acids - pharmacology; Hydroxyeicosatetraenoic Acids - physiology; Hypoxia; Lipoxygenase Inhibitors - pharmacology; Masoprocol - pharmacology; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Mitogen-activated protein kinases; Muscle, Smooth, Vascular - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Nitriles - pharmacology; Proliferation; Pulmonary Artery - cytology; Rabbits; Time Factors; Vertebrates: endocrinology
• ISSN: 0952-3278; 1532-2823
• DOI: 10.1016/j.plefa.2011.10.001

Abstract 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% O2 )-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.