Relative antithrombotic effect of soluble GPVI dimer compared with anti-GPVI antibodies in mice
Relative antithrombotic effect of soluble GPVI dimer compared with anti-GPVI antibodies in mice
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DOI：
10.1182/blood-2004-06-2391
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发表时间：
2005-02-15
期刊：
影响因子：
20.3
通讯作者：
Nieswandt, B
中科院分区：
文献类型：
--
作者：
Grüner, S;Prostredna, M;Nieswandt, B
糖蛋白VI（GPVI）是一种重要的血小板胶原受体，因此，抑制GPVI-胶原相互作用可能是一种有吸引力的抗血栓形成策略。我们先前已经表明，用抗体靶向GPVI导致受体的耗尽和小鼠的长期抗血栓保护。干扰GPVI胶原相互作用的替代剂可能是可溶性GPVI，其充当竞争性抑制剂，从而避免对血小板的不期望的作用。为了测试这一点，我们表达了可溶性二聚体人GPVI，其包含与人免疫球蛋白Fc结构域融合的受体的胞外结构域（GPVI-Fc），并将其抗血栓形成潜力与小鼠中的抗GPVI抗体的抗血栓形成潜力进行了比较。与最近的一份报告相反，我们通过活体荧光显微镜和超声流量测量发现，GPVI-Fc对血小板粘附和损伤动脉壁血栓形成没有影响，而抗GPVI抗体深刻地抑制了这些过程。用包含小鼠GPVI的细胞外结构域和人IgG-Fc的融合蛋白获得了类似的结果。这表明直接靶向GPVI提供了比可溶性GPVI二聚体显著更强的针对动脉血栓形成的保护。(C)2005年，美国血液学会。
Glycoprotein VI (GPVI) is an essential platelet collagen receptor; therefore, the inhibition of GPVI-collagen interactions may be an attractive antithrombotic strategy. We have previously shown that targeting of GPVI with antibodies leads to the depletion of the receptor and to longterm antithrombotic protection in mice. An alternative agent to interfere with GPVI collagen interactions might be soluble GPVI acting as a competitive, inhibitor, thereby averting undesired effects on platelets. To test this, we expressed soluble dimeric human GPVI, comprising the extracellular domain of the receptor fused to the human immunoglobulin Fc domain (GPVI-Fc), and compared its antithrombotic potential with that of anti-GPVI antibodies in mice. In contrast to a recent report, we found by intravital fluorescence microscopy and ultrasonic flow measurements that GPVI-Fc had no effect on platelet adhesion and thrombus formation at the injured arterial wall, whereas anti-GPVI antibodies profoundly inhibited these processes. Similar results were obtained with a fusion protein comprising the extracellular domain of mouse GPVI and human IgG-Fc. This indicates that direct targeting of GPVI provides significantly stronger protection against arterial thrombosis than soluble GPVI dimer. (C) 2005 by The American Society of Hematology.