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12‐LOX Modulates FcγRIIa‐mediated Platelet Response
Author(s) -
Yeung Jennifer,
Tourdot Benjamin,
FernandezPerez Pilar,
Maloney David,
Holman Theodore,
McKenzie Steven,
Holinstat Michael
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.941.1
Subject(s) - platelet , platelet activation , immune system , thrombosis , medicine , pharmacology , immunology
FcγRIIa is central to the pathophysiology of a number of immune‐mediated thrombocytopenia and thrombosis (ITT) syndromes. ITT is associated with significant morbidity and mortality due to unwanted platelet‐mediated vessel occlusion. Therapeutic approaches for prevention of ITT remain a challenge since the currently approved treatment reduces, but does not eliminate incidence of thrombosis and is complicated by prolonged bleeding risk. Hence novel therapeutic strategies for prevention of ITT are warranted. Our lab has demonstrated that platelet 12‐lipoxygenase (12‐LOX), an enzyme that oxidizes free fatty acid, is an important regulator of FcγRIIa–mediated platelet activation in humans and mice. The pharmacological inhibition of 12‐LOX in human and genetic ablation of 12‐LOX in transgenic mouse (FcR/ALOX12 ‐/‐ ) platelets resulted in significant decrease in activation of FcγRIIa‐mediated effectors (PLCγ2, calcium mobilization, Rap1, and PKC) as well as platelet aggregation. To further evaluate the role of 12‐LOX regulation in this pathway, a pull‐down of 12‐LOX was performed to assess protein interactions that are required for FcγRIIa‐mediated platelet activation. A number of novel proteins were found to interact with 12‐LOX in an activation‐dependent manner. Our data supports an essential role for 12‐LOX in regulating FcγRIIa‐mediated platelet function through its complex formation, and demonstrates 12‐LOX as a viable novel therapeutic target to prevent immune‐mediated thromboses such as heparin‐induced thrombocytopenia and thrombosis (HITT) and sepsis.