12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity.

Yeung J, Apopa PL, Vesci J, Stolla M, Rai G, Simeonov A, Jadhav A, Fernandez-Perez P, Maloney DJ, Boutaud O, Holman TR, Holinstat M
Thromb Haemost. 2013 110 (3): 569-81

PMID: 23784669 · PMCID: PMC3960303 · DOI:10.1160/TH13-01-0014

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.

MeSH Terms (17)

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid Animals Arachidonate 12-Lipoxygenase Blood Platelets Cyclooxygenase 1 Eicosanoids Flow Cytometry Humans Mice Mice, Transgenic Platelet Activation Platelet Adhesiveness Platelet Aggregation Platelet Membrane Glycoproteins Receptors, Thrombin Thrombosis Time Factors

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