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12-hydroxyeicosatetraenoic acid is associated with variability in aspirin-induced platelet inhibition.

Maskrey BH, Rushworth GF, Law MH, Treweeke AT, Wei J, Leslie SJ, Megson IL, Whitfield PD - J Inflamm (Lond) (2014)

Bottom Line: 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.Low-dose aspirin administration not only inhibited TxA2 generation but also decreased the production of 12-HETE.The study also highlights a potentially important mechanism by which aspirin impacts upon eicosanoid generation.

View Article: PubMed Central - PubMed

Affiliation: Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH UK.

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.

No MeSH data available.


Inhibition of 12-LOX reduces platelet aggregation. Platelets were pre-treated with or without 100 μM baicalein prior to aggregation with 1.25 μg/ml collagen. Platelet aggregation was measured for 6 min and data expressed as (A) area under the curve (AUC). (n = 3, mean ± SEM). Panel B shows a representative aggregometry trace.
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Fig4: Inhibition of 12-LOX reduces platelet aggregation. Platelets were pre-treated with or without 100 μM baicalein prior to aggregation with 1.25 μg/ml collagen. Platelet aggregation was measured for 6 min and data expressed as (A) area under the curve (AUC). (n = 3, mean ± SEM). Panel B shows a representative aggregometry trace.

Mentions: To investigate a functional role for 12-HETE in platelet aggregation, 12-LOX was inhibited using baicalein. As shown in Figure 4A, treatment with 100 μM baicalein significantly reduced (P = 0.032) platelet aggregation in response to collagen activation (mean reduction in aggregation =55 ± 11%). Figure 4B shows representative aggregometry traces. To confirm effective baicalein-induced inhibition of 12-LOX, levels of 12-HETE were measured by LC-MS/MS and revealed a mean reduction in 12-HETE to 52 ± 6% with baicalein treatment.Figure 4


12-hydroxyeicosatetraenoic acid is associated with variability in aspirin-induced platelet inhibition.

Maskrey BH, Rushworth GF, Law MH, Treweeke AT, Wei J, Leslie SJ, Megson IL, Whitfield PD - J Inflamm (Lond) (2014)

Inhibition of 12-LOX reduces platelet aggregation. Platelets were pre-treated with or without 100 μM baicalein prior to aggregation with 1.25 μg/ml collagen. Platelet aggregation was measured for 6 min and data expressed as (A) area under the curve (AUC). (n = 3, mean ± SEM). Panel B shows a representative aggregometry trace.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4209229&req=5

Fig4: Inhibition of 12-LOX reduces platelet aggregation. Platelets were pre-treated with or without 100 μM baicalein prior to aggregation with 1.25 μg/ml collagen. Platelet aggregation was measured for 6 min and data expressed as (A) area under the curve (AUC). (n = 3, mean ± SEM). Panel B shows a representative aggregometry trace.
Mentions: To investigate a functional role for 12-HETE in platelet aggregation, 12-LOX was inhibited using baicalein. As shown in Figure 4A, treatment with 100 μM baicalein significantly reduced (P = 0.032) platelet aggregation in response to collagen activation (mean reduction in aggregation =55 ± 11%). Figure 4B shows representative aggregometry traces. To confirm effective baicalein-induced inhibition of 12-LOX, levels of 12-HETE were measured by LC-MS/MS and revealed a mean reduction in 12-HETE to 52 ± 6% with baicalein treatment.Figure 4

Bottom Line: 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.Low-dose aspirin administration not only inhibited TxA2 generation but also decreased the production of 12-HETE.The study also highlights a potentially important mechanism by which aspirin impacts upon eicosanoid generation.

View Article: PubMed Central - PubMed

Affiliation: Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH UK.

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.

No MeSH data available.