title: Chronic hypoxia activates lung 15-lipoxygenase, which catalyzes production of 15-HETE and enhances constriction in neonatal rabbit pulmonary arteries.
abstract: Hypoxia causes localized pulmonary arterial (PA) constriction to divert blood flow to optimally ventilated regions of the lung. The biochemical mechanisms for this have remained elusive, especially during prolonged exposures to reduced PO2. We have evidence that subacute hypoxia activates 15-lipoxygenase (15-LO) in small PAs of neonatal rabbits maintained for 9 days in hypoxic environments (FiO2=0.12) compared with siblings raised under normoxia. PA microsomal products of 15-LO, 15-hydroxyeicosatetraenoic acid (HETE), 11,14,15-trihydroxyeicosatrienoic acid (THETA), and 11,12,15-THETA were identified by gas chromatography/mass spectrometry. Increased amounts of these products are synthesized in vivo and in vitro by the lungs of animal raised in hypoxic versus normoxic environments. 15-HETE formation is attenuated by lipoxygenase, but not cytochrome P450 or cyclooxygenase inhibitors. Activation of 15-LO is associated with translocation of the enzyme from the cytosol to membrane as seen by Western immunoblotting. Immunohistochemical analysis demonstrates that 15-LO expression is clearly localized in vascular cells in lungs from normoxic and hypoxic kits. 15-HETE causes concentration-dependent constriction of PA rings from animals exposed to hypoxic but not normoxic environments. In addition, lipoxygenase inhibitors reduce phenylephrine-induced constriction of PA rings. Therefore, subacute hypoxia increases expression of and activates 15-LO, and enhances sensitivity of pulmonary arteries to its product, 15-HETE. Because 15-HETE is a constrictor in this vascular bed, it may play an important role in hypoxia-induced pulmonary vasoconstriction in rabbit kits. Although a clear causal relationship remains to be demonstrated, these data suggest a previously unrecognized role for 15-LO in hypoxic vasoconstriction in neonatal mammals.
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wis 53226, USA.
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
authors.forename: Meetha
authors.initials: M
authors.lastname: Medhora
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
authors.forename: Nancy
authors.initials: N
authors.lastname: Spitzbarth
authors.forename: John E
authors.initials: JE
authors.lastname: Baker
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D002384:Catalysis; D015687:Cell Hypoxia; D004789:Enzyme Activation; D008401:Gas Chromatography-Mass Spectrometry; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis* / Q000494:pharmacology; D007425:Intracellular Membranes / Q000201:enzymology; D008168:Lung / Q000033:anatomy & histology / Q000201:enzymology*; D008861:Microsomes / Q000378:metabolism; D021381:Protein Transport; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D013997:Time Factors; D014661:Vasoconstriction
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001093:Arachidonate 15-Lipoxygenase