Inhibition of leukocyte C2GlcNAcT--l reduces thrombosis

描述（由申请人提供）： 动脉血栓引起的不稳定型心绞痛、心肌梗死、中风和猝死是世界范围内发病率和死亡率最高的原因，尽管有各种溶栓、抗血小板和抗凝药物可用。因此，需要新的预防和治疗方法来减少血栓形成事件。越来越多的证据表明，炎症分子P-选择素及其配体P-选择素糖蛋白配体-1（PSGL-1）参与多种血栓形成过程，包括组织因子（TF）的产生和转移。PSGL-1具有一个特定的“O-连接”寡糖，其末端是唾液酸化的Lewis-X部分，这对于PSGL-1与P-选择素的结合至关重要。白细胞核心2 1-6-N-葡糖胺基转移酶-I（C2 GlcNAcT-I），一种高尔基体酶，是将该结合表位附着到PSGL-1所必需的。在我们的初步研究中，我们发现C2 GlcNAcT-I在C57 BL/6小鼠中的缺乏延长血浆凝血时间并抑制血栓形成。我们假设白细胞C2 GlcNAcT-I参与单核细胞组织因子（TF）的产生和循环TF携带微粒（MP）在动脉粥样硬化小鼠血栓中的归巢。白细胞C2 GlcNAcT-I缺陷或其活性抑制可改善载脂蛋白E缺陷（apoE-/-）小鼠的促凝状态并抑制血栓形成。抑制C2 GlcNAcT-I可能是预防和治疗动脉粥样硬化中动脉血栓形成的一种新方法。

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.