Inhibition of leukocyte C2GlcNAcT--l reduces thrombosis

DESCRIPTION (provided by applicant): Arterial thrombi bring about unstable angina, myocardial infarction, stroke and sudden death, which are the most common causes of morbidity and mortality worldwide, despite the availability of various thrombolytic, antiplatelet and anticoagulant drugs. Therefore, new preventive and therapeutic approaches are needed to reduce thrombotic events. Accumulating evidence suggests that the inflammatory molecule P-selectin and its ligand P-selectin glycoprotein ligand-1 (PSGL-1) participate in a variety of thrombotic processes including tissue factor (TF) generation and transfer. PSGL-1 has a specific "O-linked" oligosaccharide terminating with a sialyl Lewis-X moiety, which is crucial for its binding to P-selectin. Leukocyte core 2 1-6-N-glucosaminyltransferase-I (C2GIcNAcT-I), a Golgi enzyme, is required for the attachment of this binding epitope to PSGL-1. In our pilot study, we have found that deficiency of C2GIcNAcT-I in C57BL/6 mice prolongs plasma clotting time and inhibits thrombus formation. We hypothesize that leukocyte C2GIcNAcT-I is involved in monocytic tissue factor (TF) production and homing of circulating TF-carrying microparticles (MPs) to thrombi in atherosclerotic mice. Deficiency of leukocyte C2GIcNAcT-I or inhibition of its activity results in amelioration of the procoagulant state and suppression of thrombus formation in apolipoprotein E deficient (apoE-/-) mice. Inhibition of C2GIcNAcT-I may be a novel approach for preventive and therapeutic interventions in arterial thrombosis in atherosclerosis.