Cytosolic phospholipase A2 (cPLA2) releases arachidonic acid (AA) from phospholipids in cell membranes. To assess the role of cPLA2 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 cPLA2α. LMBO increased LPVR in cPLA2α+/+ mice but not in cPLA2α–/– mice. cPLA2α+/+ mice were better able to maintain systemic oxygenation during LMBO than were cPLA2α–/– mice. Administration of a cPLA2 inhibitor, arachidonyl trifluoromethyl ketone, blocked the LMBO-induced increase in LPVR in wild-type mice, while exogenous AA restored HPV in cPLA2α–/– mice. Intravenous angiotensin II infusion increased PVR similarly in cPLA2α+/+ and cPLA2α–/– mice. Inhibitors of cyclooxygenase or nitric oxide synthase restored HPV in cPLA2α–/– mice. Breathing 10% oxygen for 3 weeks produced less right ventricular hypertrophy in cPLA2α–/– than in cPLA2α+/+ mice, but restored HPV in cPLA2α–/– mice despite the continued absence of cPLA2 activity. These results indicate that cPLA2 contributes to the murine pulmonary vasoconstrictor response to hypoxia. Augmenting pulmonary vascular tone restores HPV in the absence of cPLA2 activity.
Fumito Ichinose, Roman Ullrich, Adam Sapirstein, Rosemary C. Jones, Joseph V. Bonventre, Charles N. Serhan, Kenneth D. Bloch, Warren M. Zapol
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