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Thromb Haemost. 2013 Sep;110(3):569-81. doi: 10.1160/TH13-01-0014. Epub 2013 Jun 20.

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

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  • 1Michael Holinstat, Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, 1020 Locust Street, Suite 394, Jefferson Alumni Hall, Philadelphia, PA, USA, Tel.: +1 215 955 6121, Fax: +1 215 955 9170, E-mail: michael.holinstat@jefferson.edu.

Abstract

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.

PMID:
23784669
[PubMed - indexed for MEDLINE]
PMCID:
PMC3960303
Free PMC Article
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