title: 12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity.
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.
authors.affiliation: Michael 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.
authors.forename: J
authors.initials: J
authors.lastname: Yeung
authors.forename: P L
authors.initials: PL
authors.lastname: Apopa
authors.forename: J
authors.initials: J
authors.lastname: Vesci
authors.forename: M
authors.initials: M
authors.lastname: Stolla
authors.forename: G
authors.initials: G
authors.lastname: Rai
authors.forename: A
authors.initials: A
authors.lastname: Simeonov
authors.forename: A
authors.initials: A
authors.lastname: Jadhav
authors.forename: P
authors.initials: P
authors.lastname: Fernandez-Perez
authors.forename: D J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: O
authors.initials: O
authors.lastname: Boutaud
authors.forename: T R
authors.initials: TR
authors.lastname: Holman
authors.forename: M
authors.initials: M
authors.lastname: Holinstat
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000737:chemistry; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015539:Platelet Activation; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism; D013997:Time Factors
chemical_list: D015777:Eicosanoids; D010980:Platelet Membrane Glycoproteins; D018179:Receptors, Thrombin; C098341:platelet membrane glycoprotein VI; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D051545:Cyclooxygenase 1; C112908:protease-activated receptor 4