Cytosolic phospholipase A(2) in hypoxic pulmonary vasoconstriction.
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.
Ichinose
Fumito
F
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ichinose@etherdome.mgh.harvard.edu
Ullrich
Roman
R
Sapirstein
Adam
A
Jones
Rosemary C
RC
Bonventre
Joseph V
JV
Serhan
Charles N
CN
Bloch
Kenneth D
KD
Zapol
Warren M
WM
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
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