Human platelets generate phospholipid-esterified prostaglandins via cyclooxygenase-1 that are inhibited by low dose aspirin supplementation

Oxidized phospholipids (oxPLs) generated nonenzymatically display pleiotropic biological actions in inflammation. Their generation by cellular cyclooxygenases (COXs) is currently unknown. To determine whether platelets generate prostaglandin (PG)-containing oxPLs, then characterize their structures and mechanisms of formation, we applied precursor scanning-tandem mass spectrometry to lipid extracts of agonist-activated human platelets. Thrombin, collagen, or ionophore activation stimulated generation of families of PGs comprising PGE2 and D2 attached to four phosphatidylethanolamine (PE) phospholipids (16:0p/, 18:1p/, 18:0p/, and 18:0a/). They formed within 2 to 5 min of activation in a calcium, phospholipase C, p38 MAP kinases, MEK1, cPLA2, and src tyrosine kinase-dependent manner (28.1 ± 2.3 pg/2 × 108 platelets). Unlike free PGs, they remained cell associated, suggesting an autocrine mode of action. Their generation was inhibited by in vivo aspirin supplementation (75 mg/day) or in vitro COX-1 blockade. Inhibitors of fatty acyl reesterification blocked generation significantly, while purified COX-1 was unable to directly oxidize PE in vitro. This indicates that they form in platelets via rapid esterification of COX-1 derived PGE2/D2 into PE. In summary, COX-1 in human platelets acutely mediates membrane phospholipid oxidation via formation of PG-esterified PLs in response to pathophysiological agonists. Oxidized phospholipids (oxPLs) generated nonenzymatically display pleiotropic biological actions in inflammation. Their generation by cellular cyclooxygenases (COXs) is currently unknown. To determine whether platelets generate prostaglandin (PG)-containing oxPLs, then characterize their structures and mechanisms of formation, we applied precursor scanning-tandem mass spectrometry to lipid extracts of agonist-activated human platelets. Thrombin, collagen, or ionophore activation stimulated generation of families of PGs comprising PGE2 and D2 attached to four phosphatidylethanolamine (PE) phospholipids (16:0p/, 18:1p/, 18:0p/, and 18:0a/). They formed within 2 to 5 min of activation in a calcium, phospholipase C, p38 MAP kinases, MEK1, cPLA2, and src tyrosine kinase-dependent manner (28.1 ± 2.3 pg/2 × 108 platelets). Unlike free PGs, they remained cell associated, suggesting an autocrine mode of action. Their generation was inhibited by in vivo aspirin supplementation (75 mg/day) or in vitro COX-1 blockade. Inhibitors of fatty acyl reesterification blocked generation significantly, while purified COX-1 was unable to directly oxidize PE in vitro. This indicates that they form in platelets via rapid esterification of COX-1 derived PGE2/D2 into PE. In summary, COX-1 in human platelets acutely mediates membrane phospholipid oxidation via formation of PG-esterified PLs in response to pathophysiological agonists. Prostaglandins (PGs) are a family of lipid signaling mediators generated by cyclooxygenase (COX) enzymes, COX-1 and -2. They play central roles in health, as well as in diseases including cancer and atherosclerosis. Until recently, they were considered to only exist as free acid mediators, secreted from cells to activate G-protein coupled receptors in a paracrine manner. In 2005, Kozak et al. (1Kozak K.R. Rowlinson S.W. Marnett L.J. Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2.J. Biol. Chem. 2000; 275: 33744-33749Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar, 2Kozak K.R. Crews B.C. Morrow J.D. Wang L.H. Ma Y.H. Weinander R. Jakobsson P.J. Marnett L.J. Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides.J. Biol. Chem. 2002; 277: 44877-44885Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar) showed prostaglandins E2 and D2 (PGE2, PGD2) were generated in macrophage cell lines from COX-2 oxidation of endogenous arachidonyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA). The products signal differently to free PGE2 and D2; for example, PGE2-G mobilizes calcium rapidly in a PGE2-independent manner, indicating they are chemically and functionally distinct from their free acid analogs (3Hammond V.J. Morgan A.H. Lauder S. Thomas C.P. Brown S. Freeman B.A. Lloyd C.M. Davies J. Bush A. Levonen A.L. et al.Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-gamma.J. Biol. Chem. 2012; 287: 41651-41666Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 4Nirodi C.S. Crews B.C. Kozak K.R. Morrow J.D. Marnett L.J. The glyceryl ester of prostaglandin E2 mobilizes calcium and activates signal transduction in RAW264.7 cells.Proc. Natl. Acad. Sci. USA. 2004; 101: 1840-1845Crossref PubMed Scopus (105) Google Scholar). Oxidized phospholipids (oxPLs) were originally characterized as nonenzymatically-generated species present in atheromatous plaque that display potent immunomodulatory activities (5Podrez E.A. Poliakov E. Shen Z. Zhang R. Deng Y. Sun M. Finton P.J. Shan L. Febbraio M. Hajjar D.P. et al.A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions.J. Biol. Chem. 2002; 277: 38517-38523Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar, 6Watson A.D. Leitinger N. Navab M. Faull K.F. Horkko S. Witztum J.L. Palinski W. Schwenke D. Salomon R.G. Sha W. et al.Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo.J. Biol. Chem. 1997; 272: 13597-13607Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar, 7Bochkov V.N. Oskolkova O.V. Birukov K.G. Levonen A.L. Binder C.J. Stockl J. Generation and biological activities of oxidized phospholipids.Antioxid. Redox Signal. 2010; 12: 1009-1059Crossref PubMed Scopus (397) Google Scholar). Recent studies have indicated that they are also generated in a highly specific manner by cellular lipoxygenases (LOXs) in neutrophils, monocytes and platelets (8O'Donnell V.B. Murphy R.C. New families of bioactive oxidized phospholipids generated by immune cells: identification and signaling actions.Blood. 2012; 120: 1985-1992Crossref PubMed Scopus (66) Google Scholar, 9Clark S.R. Guy C.J. Scurr M.J. Taylor P.R. Kift-Morgan A.P. Hammond V.J. Thomas C.P. Coles B. Roberts G.W. Eberl M. et al.Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection.Blood. 2011; 117: 2033-2043Crossref PubMed Scopus (70) Google Scholar, 10Maskrey B.H. Bermudez-Fajardo A. Morgan A.H. Stewart-Jones E. Dioszeghy V. Taylor G.W. Baker P.R. Coles B. Coffey M.J. Kuhn H. et al.Activated platelets and monocytes generate four hydroxyphosphatidylethanolamines via lipoxygenase.J. Biol. Chem. 2007; 282: 20151-20163Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 11Morgan A.H. Dioszeghy V. Maskrey B.H. Thomas C.P. Clark S.R. Mathie S.A. Lloyd C.M. Kuhn H. Topley N. Coles B.C. et al.Phosphatidylethanolamine-esterified eicosanoids in the mouse: tissue localization and inflammation-dependent formation in Th-2 disease.J. Biol. Chem. 2009; 284: 21185-21191Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 12Morgan A.H. Hammond V.J. Morgan L. Thomas C.P. Tallman K.A. Garcia-Diaz Y.R. McGuigan C. Serpi M. Porter N.A. Murphy R.C. et al.Quantitative assays for esterified oxylipins generated by immune cells.Nat. Protoc. 2010; 5: 1919-1931Crossref PubMed Scopus (41) Google Scholar, 13Morgan L.T. Thomas C.P. Kuhn H. O'Donnell V.B. Thrombin-activated human platelets acutely generate oxidized docosahexaenoic-acid-containing phospholipids via 12-lipoxygenase.Biochem. J. 2010; 431: 141-148Crossref PubMed Scopus (60) Google Scholar, 14Thomas C.P. Morgan L.T. Maskrey B.H. Murphy R.C. Kuhn H. Hazen S.L. Goodall A.H. Hamali H.A. Collins P.W. O'Donnell V.B. Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation.J. Biol. Chem. 2010; 285: 6891-6903Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Also, oxidized cholesteryl esters formed by 15-lipoxygenase in macrophages can transfer the oxidized fatty acyl group to phospholipids (15Hutchins P.M. Murphy R.C. Cholesteryl ester acyl oxidation and remodeling in murine macrophages: formation of oxidized phosphatidylcholine.J. Lipid Res. 2012; 53: 1588-1597Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). However, oxPLs generated by COX isoforms have not been described. Furthermore, whereas COX-2 can oxidize AEA and 2-AG, the constitutive isoform COX-1 has not been shown to be a source of any esterified eicosanoids before. Herein, we used a targeted lipidomic approach to demonstrate that human platelets generate phospholipid (PL)-esterified PGE2 and PGD2 on agonist activation. Their synthesis is highly regulated, involving receptors and a number of key intracellular signaling pathways. Thus, oxPLs can be generated acutely via COX-1 and represent a new family of lipids from this important vascular signaling pathway. Lipid and fatty acid standards were purchased from Avanti Polar Lipids (Alabaster, AL) or Cayman were from receptor and were from C, and were from COX-1 and were from Cayman signaling phospholipase and p38 were from were from Lipid extracts were by a K.R. Crews B.C. Morrow J.D. Wang L.H. Ma Y.H. Weinander R. Jakobsson P.J. Marnett L.J. Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides.J. Biol. Chem. 2002; 277: 44877-44885Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar) × 2 a of min by min a of were V. were from to mass 5 to were to on a × a of min a of was and products a of phospholipids were for by on a This was by of in into the specific as of and to of were V. of and PGD2 was a 5 × The was of acid in and acid in was from to then to for 5 then to was were V. The were PGE2 and and of esterified prostaglandins in lipid extracts were by a K.R. Crews B.C. Morrow J.D. Wang L.H. Ma Y.H. Weinander R. Jakobsson P.J. Marnett L.J. Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides.J. Biol. Chem. 2002; 277: 44877-44885Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar) × 2 a of min by min min was a V. Lipids were as to or as of lipids by lipids were by coupled to an on a × a of min by min then to 5 min a of min was in mode and of and The and source were to and of in mode was were (3Hammond V.J. Morgan A.H. Lauder S. Thomas C.P. Brown S. Freeman B.A. Lloyd C.M. Davies J. Bush A. Levonen A.L. et al.Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-gamma.J. Biol. Chem. 2012; 287: 41651-41666Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar) of was in mode on the in were by the of were and were to the of studies on was from free from for into and for min was and for and the in 5 were for min then in 2 × were in the presence of for collagen, or lipid as involving signaling 2 C, acid ester p38 and 5 a min In calcium was from of cells from platelets were for 5 min then for 5 aspirin were a for of were aspirin for then a were and in vitro as then lipids as was a to 5 and were to as Lipids were by a to the a of to and then of C.P. Morgan L.T. Maskrey B.H. Murphy R.C. Kuhn H. Hazen S.L. Goodall A.H. Hamali H.A. Collins P.W. O'Donnell V.B. Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation.J. Biol. Chem. 2010; 285: 6891-6903Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). and lipids were in the The were then by of an of The were and for free or esterified PGs as Lipids were on a 5 × a of min a of were by on a of to for PGE2 and to for and of and of V. were and standards in the The were and and of in lipid extracts were by a K.R. Crews B.C. Morrow J.D. Wang L.H. Ma Y.H. Weinander R. Jakobsson P.J. Marnett L.J. Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides.J. Biol. Chem. 2002; 277: 44877-44885Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar) × 2 a of min by min min was a V. Lipids were as to as lipid extracts were then in phospholipase from was and for min Lipids were as was purified from and in L.J. R.C. M. of the of prostaglandin and prostacyclin by the and Google Scholar, R. Marnett L.J. and of PubMed Scopus Google Scholar). murine COX-2 was generated and purified as S.W. Crews B.C. Marnett L.J. The of acid in the cyclooxygenase of prostaglandin the Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). were to or was on for min 2 of in of the was to and and for min in the presence of or In the of was The was by of lipid and of of 5 of and as as PGE2 and D2 were by as In of the acid was to the the of The were and and and are of in for is as ± of was an the of was was used by as indicated in the was considered To PGs attached to human platelets were then lipids and for the of and min that on thrombin activation in this four and represent PE or PGs attached R.C. of of and Scholar). lipids were into PE and and by and four the as a PE in the min Thus, the are as and and a and are and by that family of the lipids PGE2 and PGD2 esterified to PE of in human we were unable to for of and not as in in a was as However, PGE2 and lipids on in and the PE are as a studies showed that formed on activation collagen, or to free PGE2 and PGD2 and species were was the of free and esterified PGE2 and PGD2 were 2 min activation. However, to min to free PGs, remained or to to activation standards are not we from platelets and attached and we min of thrombin for esterified were ± ± ± and ± pg/2 × 108 platelets ± for the 18:1p/, and a for four PE species of ± 2.3 pg/2 × 108 was by the platelets in or In of free PGE2 and PGD2 was into the prostaglandins are by platelets while free PGE2 and PGD2 are and generation of free and esterified PGs is to COX-1 in vitro and in PGs are by platelets. human platelets were thrombin for min The was to lipid and by C, and free PGE2/D2 generation is to aspirin in vitro. were for min aspirin to thrombin activation by lipid and of free and esterified PGE2/D2 and free PGE2/D2 generation is to COX were for min or to thrombin activation for by lipid and of free and esterified PGE2/D2 ± of and and and esterified PGE2/D2 formation in vivo is blocked by was a for of platelets and of free and esterified PGE2/D2 as in and activation thrombin for then aspirin for of a and of free and esterified PGE2/D2 is of ± and and of are as to of free PGE2 and PGD2 are as × 108 In COX including and the COX-1 inhibited formation as well as free PGE2/D2 Furthermore, a supplementation COX-1 low aspirin in vivo inhibited generation of free and esterified PGE2/D2 by platelets in response to thrombin To determine whether generation by platelets is via oxidation of PE or esterification of formed and fatty acyl were inhibited and the of purified and COX isoforms to oxidize PE in vitro of for not or were for free of fatty or showed of generation In platelets were or to generated to determine whether lipids are into PE the of activation. However, platelets generated in COX generated PGE2 and D2 from a of PGE2 to of to is in platelets of was detected in was a and this was by COX-1 as oxidation However, COX-1 not indicating directly oxidize However, was COX-1 oxidation of a formation of was was used of of esterified PGs were not indicating that esterified PGs directly via oxidation not formation, that was not Thus, is that from the COX-1 oxidize PE in a manner that This also in platelets as a for esterified formation, is to for the of the formation as esterified were not detected in the for and COX-1 for generation indicates that COX-1 oxidation of is by and that generation in platelets via reesterification of However, only generated is suggesting PGE2/D2 synthesis and into PE. activates platelets via and for or stimulated generation of esterified and free PGE2/D2 Generation of and free PGE2/D2 in response to thrombin was inhibited by the calcium not by of calcium by calcium from intracellular of was while formation This indicates that a on free and esterified PGE2/D2 blocked generation and p38 MAP phospholipase C, MEK1, and p38 MAP kinases, the a highly receptor and intracellular signaling that is for free and prostaglandins mechanisms for formation of by human is oxidized by then esterified into PE. of the lipids in intracellular COX-1 and esterification are Herein, we showed that agonist-activated human platelets generate families of oxPLs via COX-1 that esterified PGs, PGE2 and PGD2 attached to PE. They form a of receptor and intracellular signaling pathways. a new group of oxPLs and COX form in platelets in response to pathophysiological agonists. are families of bioactive lipids generated by and in vascular and immune cells (3Hammond V.J. Morgan A.H. Lauder S. Thomas C.P. Brown S. Freeman B.A. Lloyd C.M. Davies J. Bush A. Levonen A.L. et al.Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-gamma.J. Biol. Chem. 2012; 287: 41651-41666Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 7Bochkov V.N. Oskolkova O.V. Birukov K.G. Levonen A.L. Binder C.J. Stockl J. Generation and biological activities of oxidized phospholipids.Antioxid. Redox Signal. 2010; 12: 1009-1059Crossref PubMed Scopus (397) Google Scholar, 9Clark S.R. Guy C.J. Scurr M.J. Taylor P.R. Kift-Morgan A.P. Hammond V.J. Thomas C.P. Coles B. Roberts G.W. Eberl M. et al.Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection.Blood. 2011; 117: 2033-2043Crossref PubMed Scopus (70) Google Scholar, 10Maskrey B.H. Bermudez-Fajardo A. Morgan A.H. Stewart-Jones E. Dioszeghy V. Taylor G.W. Baker P.R. Coles B. Coffey M.J. Kuhn H. et al.Activated platelets and monocytes generate four hydroxyphosphatidylethanolamines via lipoxygenase.J. Biol. Chem. 2007; 282: 20151-20163Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 11Morgan A.H. Dioszeghy V. Maskrey B.H. Thomas C.P. Clark S.R. Mathie S.A. Lloyd C.M. Kuhn H. Topley N. Coles B.C. et al.Phosphatidylethanolamine-esterified eicosanoids in the mouse: tissue localization and inflammation-dependent formation in Th-2 disease.J. Biol. Chem. 2009; 284: 21185-21191Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 13Morgan L.T. Thomas C.P. Kuhn H. O'Donnell V.B. Thrombin-activated human platelets acutely generate oxidized docosahexaenoic-acid-containing phospholipids via 12-lipoxygenase.Biochem. J. 2010; 431: 141-148Crossref PubMed Scopus (60) Google Scholar, 14Thomas C.P. Morgan L.T. Maskrey B.H. Murphy R.C. Kuhn H. Hazen S.L. Goodall A.H. Hamali H.A. Collins P.W. O'Donnell V.B. Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation.J. Biol. Chem. 2010; 285: 6891-6903Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). to has not been considered that COX is a source of this the of key lipid signaling pathways. is also a new for has not been shown as a source of esterified PGs before. from COX-1 as their generation was to of this in vitro and in The primary of is in and in is rapidly to or to PGE2 and D2 C.J. Salomon R.G. Roberts L.J. of the formed from prostaglandin via the PubMed Scopus Google Scholar, R. S.R. synthesis of Chem. Scopus Google Scholar). The not PGD2 formation not and PGE2 generation from while is not C.J. Salomon R.G. Roberts L.J. of the formed from prostaglandin via the PubMed Scopus Google Scholar). and were of and not be However, as free PGE2/D2 are for platelets and purified their generation in platelets from to esterification is The of lipids are for free PGs generated by platelets (28.1 ± 2.3 pg/2 × 108 platelets). However, they are not secreted from the cells and in intracellular to Furthermore, bioactive phospholipids can signal low for example, that can and activation only of in 2000; PubMed Scopus Google Scholar). are generated within the 2 min of to the for generation of free PGE2/D2 This indicates that formation is and a in response to agonists. Their generation of esterified PGs or membrane remodeling pathways. The of signaling indicates that this is a highly and their to and COX-1 and to generation of free and esterified PGE2/D2 or coupled in vitro that COX-1 directly oxidize PE that form via reesterification of formed PGE2/D2 This is also by the of and in of PGs from PE This is aspirin in vitro and in to the and the of to esterified is that the in formation and reesterification are that and esterification are that is oxidized fatty are esterified into and whether the display for fatty or To in were used as a to PGE2 esterification into PE. However, was esterified to PE or we were unable to or that studies have shown that in lipid are present in platelets not indicating that of in fatty acid A. and in fatty acid remodeling of phospholipids and of bioactive lipids in 1997; PubMed Scopus Google Scholar). The and for prostaglandin esterification are the and is a in distinct and 2002; PubMed Scopus Google Scholar). Furthermore, COX-1 is to structures in platelets D. of prostaglandin in the J. Google Scholar). Thus, generation on intracellular In this PGE2 the in to be esterified into Thus, the of esterification also be to an of platelets to this lipid the of prostaglandin on the cell To is of by platelets they oxidized fatty as Y. J. of a of the prostaglandin 2011; PubMed Scopus Google Scholar). to a family of eicosanoids that have been in platelets and vascular cells the 5 to were generated by and in platelets families of PE and that acid or acid L.T. Thomas C.P. Kuhn H. O'Donnell V.B. Thrombin-activated human platelets acutely generate oxidized docosahexaenoic-acid-containing phospholipids via 12-lipoxygenase.Biochem. J. 2010; 431: 141-148Crossref PubMed Scopus (60) Google Scholar, 14Thomas C.P. Morgan L.T. Maskrey B.H. Murphy R.C. Kuhn H. Hazen S.L. Goodall A.H. Hamali H.A. Collins P.W. O'Donnell V.B. Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation.J. Biol. Chem. 2010; 285: 6891-6903Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). and have also been characterized in human neutrophils and monocytes (3Hammond V.J. Morgan A.H. Lauder S. Thomas C.P. Brown S. Freeman B.A. Lloyd C.M. Davies J. Bush A. Levonen A.L. et al.Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-gamma.J. Biol. Chem. 2012; 287: 41651-41666Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 9Clark S.R. Guy C.J. Scurr M.J. Taylor P.R. Kift-Morgan A.P. Hammond V.J. Thomas C.P. Coles B. Roberts G.W. Eberl M. et al.Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection.Blood. 2011; 117: 2033-2043Crossref PubMed Scopus (70) Google Scholar, 10Maskrey B.H. Bermudez-Fajardo A. Morgan A.H. Stewart-Jones E. Dioszeghy V. Taylor G.W. Baker P.R. Coles B. Coffey M.J. Kuhn H. et al.Activated platelets and monocytes generate four hydroxyphosphatidylethanolamines via lipoxygenase.J. Biol. Chem. 2007; 282: 20151-20163Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). are also generated receptor the intracellular signaling is involving and calcium, not This the signaling in COX-1 activation in platelets. Unlike free indicating that they are to This is to oxPLs, as generated by and immune cell signaling (3Hammond V.J. Morgan A.H. Lauder S. Thomas C.P. Brown S. Freeman B.A. Lloyd C.M. Davies J. Bush A. Levonen A.L. et al.Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-gamma.J. Biol. Chem. 2012; 287: 41651-41666Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 9Clark S.R. Guy C.J. Scurr M.J. Taylor P.R. Kift-Morgan A.P. Hammond V.J. Thomas C.P. Coles B. Roberts G.W. Eberl M. et al.Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection.Blood. 2011; 117: 2033-2043Crossref PubMed Scopus (70) Google Scholar, 10Maskrey B.H. Bermudez-Fajardo A. Morgan A.H. Stewart-Jones E. Dioszeghy V. Taylor G.W. Baker P.R. Coles B. Coffey M.J. Kuhn H. et al.Activated platelets and monocytes generate four hydroxyphosphatidylethanolamines via lipoxygenase.J. Biol. Chem. 2007; 282: 20151-20163Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 11Morgan A.H. Dioszeghy V. Maskrey B.H. Thomas C.P. Clark S.R. Mathie S.A. Lloyd C.M. Kuhn H. Topley N. Coles B.C. et al.Phosphatidylethanolamine-esterified eicosanoids in the mouse: tissue localization and inflammation-dependent formation in Th-2 disease.J. Biol. Chem. 2009; 284: 21185-21191Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 14Thomas C.P. Morgan L.T. Maskrey B.H. Murphy R.C. Kuhn H. Hazen S.L. Goodall A.H. Hamali H.A. Collins P.W. O'Donnell V.B. Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation.J. Biol. Chem. 2010; 285: 6891-6903Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Oxidized PLs that can from the cell membrane In the of oxidized this has to the the fatty acid the of the cell and as scavenger receptor J. Salomon R.G. Hazen S.L. The lipid of the of oxidized cell Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to their and PGE2 and PGD2 attached to PE are also to from the intracellular membrane they they membrane or as shown to oxidation of J. Z. W. D.P. L. of lipid on the of lipid a J. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). This play a in or that membrane of lipids can be be in In summary, COX-1 was to generate a new family of oxPLs in platelets. The identification of new the for the of PGs membrane and whether be a distinct for in acid glycerol cyclooxygenase phospholipase acid acid oxidized phospholipids phosphatidylethanolamine prostaglandin prostaglandin D2 prostaglandin E2 phospholipid

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.