Hypoxia promotes rabbit pulmonary artery smooth muscle cells proliferation through a 15-LOX-2 product 15(S)-hydroxyeicosatetraenoic acid.
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.
Department of Biopharmaceutical Sciences, College of Pharmacy, Nangang District, Harbin Medical University, Harbin, China.
Ruihui
R
Shan
Li
L
Chen
Xinyu
X
Li
Hong
H
Wu
Qingcheng
Q
Liang
Xiaobo
X
Tang
D000818:Animals; D000831:Animals, Newborn; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002109:Caffeic Acids / Q000494:pharmacology; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005419:Flavonoids / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D000860:Hypoxia; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology; D011817:Rabbits; D013997:Time Factors
D002070:Butadienes; D002109:Caffeic Acids; D005419:Flavonoids; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D009570:Nitriles; C113580:U 0126; C099255:cinnamyl-3,4-dihydroxycyanocinnamate; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D009637:Masoprocol; D001093:Arachidonate 15-Lipoxygenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one