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

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Topic:

Theme Issue
Kallikreins: Pathobiology and association to disease

DOI: http://dx.doi.org/10.1160/TH13-01-0014
Issue: 2013: 110/3 (Sep) pp. 393–622
Pages: 569-581
Ahead of Print: ###MANUSCRIPT_aheadofprint###

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

Online Supplementary Material

J. Yeung (1), P. L. Apopa (1), J. Vesci (1), M. Stolla (1), G. Rai (2), A. Simeonov (2), A. Jadhav (2), P. Fernandez-Perez (1), D. J. Maloney (2), O. Boutaud (3), T. R. Holman (4), M. Holinstat (1)

(1) Department of Medicine and Cardeza foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; (2) NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, Maryland, USA; (3) Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; (4) Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California, USA

Keywords

thrombosis, eicosanoids, aggregation, platelet activation, 12-lipoxygenase

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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