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

Aldrovandi M, Hammond VJ, Podmore H, Hornshaw M, Clark SR, Marnett LJ, Slatter DA, Murphy RC, Collins PW, O'Donnell VB
J Lipid Res. 2013 54 (11): 3085-97

PMID: 23883581 · PMCID: PMC3793613 · DOI:10.1194/jlr.M041533

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.

MeSH Terms (21)

Aspirin Blood Platelets Calcium Cyclooxygenase 1 Cyclooxygenase Inhibitors Dinoprostone Dose-Response Relationship, Drug Esterification Feedback, Physiological Humans Intracellular Space MAP Kinase Kinase 1 Phosphatidylethanolamines Phospholipids Platelet Activation Prostaglandin D2 Prostaglandins Protein Kinase C Receptor, PAR-1 src-Family Kinases Thrombin

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