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

Autor: Helen Podmore, Victoria Jayne Hammond, Robert C. Murphy, David A. Slatter, Valerie B. O'Donnell, Peter William Collins, Maceler Aldrovandi, Lawrence J. Marnett, Martin Hornshaw, Stephen Clark
Rok vydání: 2013
Předmět:
Blood Platelets
Intracellular Space
MAP Kinase Kinase 1
Phospholipid
Prostaglandin
QD415-436
Biochemistry
Dinoprostone
RS
Oxidized phospholipids
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Endocrinology
Humans
Cyclooxygenase Inhibitors
Receptor
PAR-1
Platelet
Platelet activation
PGE2/D2-PEs
Phospholipids
Protein Kinase C
Research Articles
Protein kinase C
030304 developmental biology
Feedback
Physiological
Phosphatidylethanolamine
0303 health sciences
Aspirin
Dose-Response Relationship
Drug
Esterification
Phospholipase C
biology
Prostaglandin D2
Phosphatidylethanolamines
Thrombin
Cell Biology
Platelet Activation
src-Family Kinases
chemistry
Cyclooxygenase 1
Prostaglandins
biology.protein
Calcium
lipids (amino acids
peptides
and proteins)
Cyclooxygenase
atherosclerosis
030217 neurology & neurosurgery
Zdroj: Journal of Lipid Research
Journal of Lipid Research, Vol 54, Iss 11, Pp 3085-3097 (2013)
ISSN: 0022-2275
DOI: 10.1194/jlr.m041533
Popis: 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.
Databáze: OpenAIRE
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