title: 12-hydroxyeicosatetraenoic acid is associated with variability in aspirin-induced platelet inhibition.
abstract: BACKGROUND
  Aspirin is one of the most widely used non-steroidal anti-inflammatory drugs (NSAIDs). It is also a commonly used anti-platelet drug, which inhibits the formation of the platelet activator, thromboxane A2 (TxA2) via inhibition of cyclooxygenase-1 (COX-1). However, the presence of a patient subset that fails to respond to aspirin despite reduced TxA2 concentrations suggests that the effect of aspirin might be more complex than exclusive COX-1 inhibition.
  
  
  METHODS
  In this study we evaluated the impact of in vivo oral administration of a standard anti-platelet dose (75 mg) of aspirin in healthy volunteers on the acute impact of in vitro collagen-mediated platelet aggregation and generation of platelet-derived TxA2 and the 12-lipoxygenase (LOX) metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). The eicosanoids were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  
  
  RESULTS
  Low-dose aspirin administration not only inhibited TxA2 generation but also decreased the production of 12-HETE. Furthermore, a significant correlation was observed between the levels of 12-HETE and collagen-induced platelet aggregation. Pre-treatment of platelets with the 12-LOX inhibitor, baicalein, prior to activation attenuated platelet aggregation.
  
  
  CONCLUSIONS
  These findings support a role for 12-HETE as a pro-aggregatory eicosanoid in platelet function and suggest a role for 12-HETE in variable sensitivity to aspirin. The study also highlights a potentially important mechanism by which aspirin impacts upon eicosanoid generation.
authors.affiliation: Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH UK.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Maskrey
authors.affiliation: Highland Clinical Research Facility, Inverness, UK.
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Rushworth
authors.affiliation: Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH UK.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Law
authors.affiliation: Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH UK.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Treweeke
authors.affiliation: Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH UK.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Cardiac Unit, Raigmore Hospital, Inverness, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Leslie
authors.affiliation: Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH UK.
authors.forename: Ian L
authors.initials: IL
authors.lastname: Megson
authors.affiliation: Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH UK.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Whitfield
keywords: 12-HETE; Anti-inflammatory; Aspirin; Eicosanoids; Platelet; Thromboxane