Inhibition of leukocyte C2GlcNAcT--l reduces thrombosis

描述(由申请人提供)： 动脉血栓导致不稳定性心绞痛、心肌梗死、中风和猝死，这些都是世界范围内最常见的发病率和死亡率的原因，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)参与了多种血栓形成过程，包括组织因子(TF)的产生和转移。PSGL-1有一个特殊的“O-连接”寡糖，其末端是唾液酸基Lewis-X部分，这是其与P-选择素结合的关键。白细胞核心2 1-6-N-氨基葡萄糖基转移酶-I(C2GIcNAcT-I)是一种高尔基酶，该结合表位与PSGL-1的结合是必需的。在我们的初步研究中，我们发现C57BL/6小鼠体内C2GIcNAcT-I的缺乏会延长血浆凝血时间并抑制血栓的形成。我们假设白细胞C2GIcNAcT-I参与了动脉粥样硬化小鼠单核细胞组织因子(TF)的产生和循环中携带TF的微粒(MPS)对血栓的归巢。白细胞C2GIcNAcT-I缺乏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C2GIcNAcT-I可能成为动脉粥样硬化中预防和治疗动脉血栓形成的新途径。

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.