title: Cyclooxygenase-2 Mediated Oxidation of 2-Arachidonoyl-Lysophospholipids Identifies Unknown Lipid Signaling Pathways.
abstract: Eicosanoid lipids play important roles in cellular signaling as second messengers in inflammation, immune response, vascular tone, and the CNS. Biosynthesis of eicosanoid lipids proceeds via hydrolysis of esterified arachidonic acid from phospholipids followed by oxidation of the released arachidonic acid by a variety of enzymes including cyclooxygenases (COX). Herein, we demonstrate the remarkable ability of COX-2, but not COX-1, to directly oxidize 2-arachidonoyl-lysolipids, resulting in the generation of previously unknown classes of eicosanoid-lysolipids, and provide evidence that intracellular lipases can release eicosanoids from their eicosanoid-lysolipid precursors. Importantly, genetic ablation of a phospholipase, iPLA2γ, significantly reduced the amounts of these eicosanoid-lysolipids in murine hepatic tissue and fibroblasts. Furthermore, calcium stimulation of wild-type murine lung fibroblasts produced robust increases in these eicosanoid-lysolipids, which were markedly attenuated in iPLA2γ-/-fibroblasts. Collectively, these results identify an iPLA2γ-initiated pathway generating new classes of lipid metabolites with potential signaling functions resulting from the direct COX-2 catalyzed oxidation of 2-arachidonoyl-lysolipids.
authors.affiliation: Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO 63110, USA.
authors.forename: Xinping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO 63110, USA.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Moon
authors.affiliation: Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO 63110, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jenkins
authors.affiliation: Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO 63110, USA.
authors.forename: Harold F
authors.initials: HF
authors.lastname: Sims
authors.affiliation: Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Chemistry, Washington University, Saint Louis, MO 63130, USA. Electronic address: rgross@wustl.edu.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D010084:Oxidation-Reduction; D015398:Signal Transduction
chemical_list: D015777:Eicosanoids; D008246:Lysophospholipids; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D002118:Calcium