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 ORCID: https://orcid.org/0000-0001-5907-9671, Marnett, Lawrence J., Slatter, David, Murphy, Robert C., Collins, Peter William ORCID: https://orcid.org/0000-0002-6410-1324 and O'Donnell, Valerie Bridget ORCID: https://orcid.org/0000-0003-4089-8460 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:	01 Jun 2023 19:46
URI:	https://orca.cardiff.ac.uk/id/eprint/56863

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