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

Jennifer Yeung; Patrick L. Apopa; Joanne Vesci; Moritz Stolla; Ganesha Rai; Anton Simeonov; Ajit Jadhav; Pilar Fernandez-Perez; David J. Maloney; Olivier Boutaud; Theodore R. Holman; Michael Holinstat

doi:10.1160/TH13-01-0014

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 110(03): 569-581
DOI: 10.1160/TH13-01-0014

Platelets and Blood Cells

Schattauer GmbH

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

Authors

Jennifer Yeung

¹Department of Medicine and Cardeza foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
Patrick L. Apopa

¹Department of Medicine and Cardeza foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
Joanne Vesci

¹Department of Medicine and Cardeza foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
Moritz Stolla

¹Department of Medicine and Cardeza foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

^†Currently at the Department of Pathology and Laboratory Medicine, Strong Memorial Hospital, University of Rochester, Rochester, New York, USA
Ganesha Rai

²NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, Maryland, USA
Anton Simeonov

²NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, Maryland, USA
Ajit Jadhav

²NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, Maryland, USA
Pilar Fernandez-Perez

¹Department of Medicine and Cardeza foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
David J. Maloney

²NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, Maryland, USA
Olivier Boutaud

⁴Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Theodore R. Holman

³Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California, USA
Michael Holinstat

¹Department of Medicine and Cardeza foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Abstract

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.

Keywords

Platelet activation - 12-lipoxygenase - eicosanoids - aggregation - thrombosis

Full Text

References

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