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

J Lipid Res. 2013 Nov;54(11):3085-97. doi: 10.1194/jlr.M041533. Epub 2013 Jul 24.


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.

Keywords: Oxidized phospholipids; PGE2/D2-PEs; atherosclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Cyclooxygenase Inhibitors
  • Phosphatidylethanolamines
  • Phospholipids
  • Prostaglandins
  • Receptor, PAR-1
  • phosphatidylethanolamine
  • Cyclooxygenase 1
  • src-Family Kinases
  • Protein Kinase C
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Thrombin
  • Dinoprostone
  • Aspirin
  • Prostaglandin D2
  • Calcium