title: Platelet 12-LOX is essential for FcγRIIa-mediated platelet activation.
abstract: Platelets are essential in maintaining hemostasis following inflammation or injury to the vasculature. Dysregulated platelet activity often results in thrombotic complications leading to myocardial infarction and stroke. Activation of the FcγRIIa receptor leads to immune-mediated thrombosis, which is often life threatening in patients undergoing heparin-induced thrombocytopenia or sepsis. Inhibiting FcγRIIa-mediated activation in platelets has been shown to limit thrombosis and is the principal target for prevention of immune-mediated platelet activation. In this study, we show for the first time that platelet 12(S)-lipoxygenase (12-LOX), a highly expressed oxylipin-producing enzyme in the human platelet, is an essential component of FcγRIIa-mediated thrombosis. Pharmacologic inhibition of 12-LOX in human platelets resulted in significant attenuation of FcγRIIa-mediated aggregation. Platelet 12-LOX was shown to be essential for FcγRIIa-induced phospholipase Cγ2 activity leading to activation of calcium mobilization, Rap1 and protein kinase C activation, and subsequent activation of the integrin αIIbβ3. Additionally, platelets from transgenic mice expressing human FcγRIIa but deficient in platelet 12-LOX, failed to form normal platelet aggregates and exhibited deficiencies in Rap1 and αIIbβ3 activation. These results support an essential role for 12-LOX in regulating FcγRIIa-mediated platelet function and identifies 12-LOX as a potential therapeutic target to limit immune-mediated thrombosis.
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yeung
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA;
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Tourdot
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA;
authors.forename: Pilar
authors.initials: P
authors.lastname: Fernandez-Perez
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA;
authors.forename: Joanne
authors.initials: J
authors.lastname: Vesci
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA;
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA; and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Smyrniotis
authors.affiliation: National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, MD.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Luci
authors.affiliation: National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, MD.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, MD.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, MD.
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA; and.
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA;
authors.forename: Steven E
authors.initials: SE
authors.lastname: McKenzie
authors.affiliation: Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Philadelphia, PA;
authors.forename: Michael
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*; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D015539:Platelet Activation; D010974:Platelet Aggregation; D011493:Protein Kinase C / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000276:immunology
chemical_list: C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D011493:Protein Kinase C; D051966:Phospholipase C gamma; D002118:Calcium
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