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

Aldrovandi, Maceler, Hammond, Victoria Jayne, Podmore, Helen, Hornshaw, Martin, Clark, Stephen Robert, Marnett, Lawrence J., Slatter, David, Murphy, Robert C., Collins, Peter William and O'Donnell, Valerie Bridget 2013. Human platelets generate phospholipid-esterified prostaglandins via cyclooxygenase-1 that are inhibited by low dose aspirin supplementation. Journal of Lipid Research 54 (11) , pp. 3085-3097. 10.1194/jlr.M041533

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Abstract

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.

Item Type: Article
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Oxidized phospholipids; atherosclerosis; PGE2/D2-PEs
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0022-2275
Funders: Wellcome Trust
Date of First Compliant Deposit: 30 March 2016
Last Modified: 16 Aug 2018 19:59
URI: http://orca-mwe.cf.ac.uk/id/eprint/56863

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