Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation.
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) microM 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.
Preston
Ioana R
IR
Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA. ipreston@tufts-nemc.org
Hill
Nicholas S
NS
Warburton
Rod R
RR
Fanburg
Barry L
BL
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006976:Hypertension, Pulmonary / Q000209:etiology; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D011651:Pulmonary Artery / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D001092:Arachidonate 12-Lipoxygenase