Journal
THROMBOSIS AND HAEMOSTASIS
Volume 110, Issue 3, Pages 569-581Publisher
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
DOI: 10.1160/TH13-01-0014
Keywords
Platelet activation; 12-lipoxygenase; eicosanoids; aggregation; thrombosis
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Funding
- NHLBI NIH HHS [R01 HL114405, R00 HL089457, HL089457, HL081009, P50 HL081009, K99 HL089457] Funding Source: Medline
- NIGMS NIH HHS [R01 GM105671] Funding Source: Medline
- NIMH NIH HHS [R03 MH081283, MH081283] Funding Source: Medline
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Following initial platelet activation, arachidonic acid is metabolised by cyclooxygenase-1 and 12-lipoxygenase (12-LOX). While the role of 12-LOX in the platelet is not well defined, recent evidence suggests that it may be important for regulation of platelet activity and is agonist-specific in the manner in which it regulates platelet function. Using small molecule inhibitors selective for 12-LOX and 12-LOX-deficient mice, the role of 12-LOX in regulation of human platelet activation and thrombosis was investigated. Pharmacologically inhibiting 12-LOX resulted in attenuation of platelet aggregation, selective inhibition of dense versus alpha granule secretion, and inhibition of platelet adhesion under flow for PAR4 and collagen. Additionally, 12-LOX-deficient mice showed attenuated integrin activity to PAR4-AP and convulxin compared to wild-type mice. Finally, platelet activation by PARs was shown to be differentially dependent on COX-1 and 12-LOX with PAR1 relying on COX-1 oxidation of arachidonic acid while PAR4 being more dependent on 12-LOX for normal platelet function. These studies demonstrate an important role for 12-LOX in regulating platelet activation and thrombosis. Furthermore, the data presented here provide a basis for potentially targeting 12-LOX as a means to attenuate unwanted platelet activation and clot formation.
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