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Thromb Haemost 2013; 110(03): 569-581
DOI: 10.1160/TH13-01-0014
DOI: 10.1160/TH13-01-0014
Platelets and Blood Cells
12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity
Financial Support: This work was supported in part by the National Institutes of Health grants HL089457 (MH), HL081009 (OB), MH081283 (TRH), the American Heart Association (MH), the Parenteral Drug Association Foundation (MH), and the Cardeza Foundation for Hematologic Research (MH).
Further Information
Publication History
Received:
07 January 2013
Accepted after major revision:
30 May 2013
Publication Date:
22 November 2017 (online)
Summary
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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