Dimeric Glycoprotein VI Binds to Collagen but Not to Fibrin
Dimeric Glycoprotein VI Binds to Collagen but Not to Fibrin
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DOI：
10.1160/th17-04-0302
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发表时间：
2018-02-01
影响因子：
6.7
通讯作者：
Siess, Wolfgang
中科院分区：
文献类型：
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作者：
Ebrahim, Mariam;Jamasbi, Janina;Siess, Wolfgang
血小板膜糖蛋白VI(GPVI)在动脉粥样硬化血栓形成中起决定性的胶原受体作用。除了胶原，受损的动脉粥样硬化斑块暴露出组织因子(TF)，触发纤维蛋白的形成。最近的两项研究报道，血小板GPVI还作为纤维蛋白受体发挥作用，这将重要地拓宽GPVI靶向抗血栓药物的作用模式。我们研究了两种GPVI融合蛋白在静态和动脉血流条件下与纤维蛋白的结合。纤维蛋白是由纯化的纤维蛋白原制备的，或更多地由内源性纤维蛋白原通过凝血酶凝固血浆而产生的。纤维蛋白的形成也是通过将涂有TF涂层的表面或人类动脉粥样硬化斑块切片暴露于动脉血流中而触发的。通过结合研究和先进的光学成像，我们发现来自IgG1(GPVI-FC1)或IgG2(GPVI-FC2)的重组二聚体GPVI-Fc融合蛋白可与胶原纤维结合，但不能与三家供应商纯化的纤维蛋白原制备的纤维蛋白结合，也不能与血浆中凝血酶形成的生理性纤维蛋白结合，也不能与TF或动脉粥样硬化斑块切片暴露于动脉血流中触发。我们的发现不支持二聚体血小板GPVI作为纤维蛋白受体的作用。这对于了解斑块触发的血小板血栓形成是重要的，并对未来使用重组GPVI-Fc和抗GPVI抗体进行GPVI靶向治疗具有临床意义。
Platelet glycoprotein VI (GPVI) acts as a decisive collagen receptor in atherothrombosis. Besides collagen, injured atherosclerotic plaques expose tissue factor (TF) that triggers fibrin formation. Two recent studies reported that platelet GPVI also functions as fibrin receptor, which would importantly widen the mode of action of GPVI-targeted antithrombotic drugs. We studied the binding of two GPVI fusion proteins to fibrin under static and arterial flow conditions. Fibrin was prepared from purified fibrinogen or generated more physiologically from endogenous fibrinogen by coagulating plasma with thrombin. Fibrin formation was also triggered by exposing TF-coated surfaces or human atherosclerotic plaque slices to arterially flowing blood. By binding studies and advanced optical imaging, we found that recombinant dimeric GPVI-Fc fusion proteins with Fc from either IgG1 (GPVI-Fc1) or IgG2 (GPVI-Fc2) bound to collagen fibres, but neither to fibrin prepared from purified fibrinogen obtained from three suppliers, nor to physiological fibrin formed by thrombin in plasma or triggered by exposing TF or atherosclerotic plaque slices to arterially flowing blood. Our findings do not support a role of dimeric platelet GPVI as receptor for fibrin. This is important for the understanding of plaque-triggered platelet thrombus formation and is clinically relevant for future GPVI-targeting therapies with recombinant GPVI-Fc and anti-GPVI antibodies.