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Chronic hypoxia activates lung 15-lipoxygenase, which catalyzes production of 15-HETE and enhances constriction in neonatal rabbit pulmonary arteries. Circ Res 2003 May 16;92(9):992-1000

Date

04/12/2003

Pubmed ID

12690037

DOI

10.1161/01.RES.0000070881.65194.8F

Scopus ID

2-s2.0-0037687982   127 Citations

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.

Author List

Zhu D, Medhora M, Campbell WB, Spitzbarth N, Baker JE, Jacobs ER

Authors

John E. Baker PhD Professor in the Surgery department at Medical College of Wisconsin
William B. Campbell PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Elizabeth R. Jacobs MD Associate Dean, Professor in the Medicine department at Medical College of Wisconsin
Meetha M. Medhora PhD Professor in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Arachidonate 15-Lipoxygenase
Arachidonic Acid
Catalysis
Cell Hypoxia
Enzyme Activation
Gas Chromatography-Mass Spectrometry
Hydroxyeicosatetraenoic Acids
Intracellular Membranes
Lung
Microsomes
Protein Transport
Pulmonary Artery
Rabbits
Time Factors
Vasoconstriction
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a