Tumor necrosis factor-α-converting enzyme (ADAM17) mediates GPIbα shedding from platelets in vitro and in vivo
Tumor necrosis factor-α-converting enzyme (ADAM17) mediates GPIbα shedding from platelets in vitro and in vivo
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DOI：
10.1161/01.res.0000143899.73453.11
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发表时间：
2004-10-01
影响因子：
20.1
通讯作者：
Wagner, DD
中科院分区：
文献类型：
--
作者：
Bergmeier, W;Piffath, CL;Wagner, DD
血小板受体糖蛋白（GP）Ib-V-IX与血管损伤部位暴露的血管性血友病因子的相互作用是止血塞起始的重要步骤。GPI α亚基的蛋白水解切割（脱落）在>25年前首次被描述，然而，介导该事件的蛋白酶及其生理功能尚未阐明。我们最近报道了血小板储存或线粒体损伤诱导的GPI α脱落涉及血小板源性金属蛋白酶。在这里，我们表明，GPI β脱落响应线粒体损伤或生理活化抑制血小板从嵌合小鼠，表达无活性的肿瘤坏死因子-α转化酶（TACE（Δ Zn/Δ Zn））的血细胞中。在存在2种强效TACE抑制剂（TAP 1和TMI-1）的情况下，小鼠和人血小板的脱落也受到抑制。我们的数据进一步表明，TACE在体内GPI α表达的调节中是重要的，因为我们观察到TACE（DeltaZn/DeltaZn）嵌合体的血浆中可溶性GPI α（glycocalicin）减少约90%，以及循环血小板上GPI α的水平显著增加。相反，从活化血小板脱落的P-选择素不受TACE突变的影响。损伤的TACE（DeltaZn/DeltaZn）血小板的进一步特征在于小鼠输血后恢复和止血功能显著改善。总之，我们的数据表明TACE在血小板中表达，并且它是介导GPI α脱落的关键酶。
Interaction of the platelet receptor glycoprotein (GP) Ib-V-IX with von Willebrand factor exposed at a site of vascular injury is an essential step in the initiation of a hemostatic plug. Proteolytic cleavage (shedding) of the GPIbalpha subunit was first described >25 years ago, the protease mediating this event as well as its physiological function, however, have not been elucidated. We reported recently that shedding of GPIbalpha induced by platelet storage or mitochondrial injury involves a platelet-derived metalloproteinase(s). Here we show that GPIbalpha shedding in response to mitochondrial injury or physiological activation is inhibited in platelets obtained from chimeric mice, which express inactive tumor necrosis factor-alpha converting enzyme (TACE(DeltaZn/DeltaZn)) in blood cells only. Shedding was also inhibited in mouse and human platelets in the presence of 2 potent TACE inhibitors: TAP1 and TMI-1. Our data further suggest that TACE is important in the regulation of GPIbalpha expression in vivo because we observed an approximate to90% reduction in soluble GPIbalpha (glycocalicin) in plasma of TACE(DeltaZn/DeltaZn) chimeras as well as significantly increased levels of GPIbalpha on circulating platelets. In contrast, shedding of P-selectin from activated platelets was not affected by the mutation in TACE. Damaged TACE(DeltaZn/DeltaZn) platelets were further characterized by a markedly improved post-transfusion recovery and hemostatic function in mice. In conclusion, our data demonstrate that TACE is expressed in platelets and that it is the key enzyme mediating shedding of GPIbalpha.