title: Cytosolic phospholipase A(2) in hypoxic pulmonary vasoconstriction.
abstract: Cytosolic phospholipase A(2) (cPLA(2)) releases arachidonic acid (AA) from phospholipids in cell membranes. To assess the role of cPLA(2) in hypoxic pulmonary vasoconstriction (HPV), we measured the increase in left lung pulmonary vascular resistance (LPVR) before and during hypoxia produced by left main stem bronchus occlusion (LMBO) in mice with and without a targeted deletion of the PLA2g4a gene that encodes cPLA(2alpha). LMBO increased LPVR in cPLA(2alpha)(+/+) mice but not in cPLA(2alpha)(-/-) mice. cPLA(2alpha)(+/+) mice were better able to maintain systemic oxygenation during LMBO than were cPLA(2alpha)(-/-) mice. Administration of a cPLA(2) inhibitor, arachidonyl trifluoromethyl ketone, blocked the LMBO-induced increase in LPVR in wild-type mice, while exogenous AA restored HPV in cPLA(2alpha)(-/-) mice. Intravenous angiotensin II infusion increased PVR similarly in cPLA(2alpha)(+/+) and cPLA(2alpha)(-/-) mice. Inhibitors of cyclooxygenase or nitric oxide synthase restored HPV in cPLA(2alpha)(-/-) mice. Breathing 10% oxygen for 3 weeks produced less right ventricular hypertrophy in cPLA(2alpha)(-/-) than in cPLA(2alpha)(+/+) mice, but restored HPV in cPLA(2alpha)(-/-) mice despite the continued absence of cPLA(2) activity. These results indicate that cPLA(2) contributes to the murine pulmonary vasoconstrictor response to hypoxia. Augmenting pulmonary vascular tone restores HPV in the absence of cPLA(2) activity.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ichinose@etherdome.mgh.harvard.edu
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Roman
authors.initials: R
authors.lastname: Ullrich
authors.forename: Adam
authors.initials: A
authors.lastname: Sapirstein
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Jones
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Warren M
authors.initials: WM
authors.lastname: Zapol
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology*; D015777:Eicosanoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D005838:Genotype; D000860:Hypoxia; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000201:enzymology*; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism* / Q000502:physiology*; D013997:Time Factors; D014661:Vasoconstriction
chemical_list: D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D000804:Angiotensin II; D010741:Phospholipases A; D010100:Oxygen; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin