The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation
The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation
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DOI：
10.1182/blood-2008-07-169359
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发表时间：
2009-05-21
期刊：
影响因子：
20.3
通讯作者：
Miyata, Toshiyuki
中科院分区：
文献类型：
--
作者：
Banno, Fumiaki;Chauhan, Anil K.;Miyata, Toshiyuki
ADAMTS13是一种多结构域蛋白酶，通过卵裂血管性血友病因子（VWF）来限制血小板形成。我们之前鉴定了2种类型的小鼠Adamts13基因：129/ sv -株Adamts13基因编码具有与人类Adamts13相同结构域的长形Adamts13，而C57BL/6-株Adamts13基因编码缺乏远端c端结构域的短形Adamts13。为了评估ADAMTS13远端c端结构域的生理意义，我们生成并分析了129只携带短型ADAMTS13的遗传背景同源小鼠（ADAMTS13 (S/S)）。与野生型129/Sv小鼠（Adamts13(L/L)）类似，与129/Sv遗传背景缺乏Adamts13的小鼠（Adamts13(-/-)）相比，Adamts13S/S血浆中没有超大的VWF多聚体。然而，与Adamts13（L/L）相比，在5000 s（-1）剪切速率下，Adamts13（s / s）的体外血栓形成速度加快。体内氯化铁损伤小动脉血栓形成和胶原+肾上腺素刺激引起的血小板减少，Adamts13组（S/S）比Adamts13组（L/L）更明显，但比Adamts13组（-/-）少。这些结果表明，c端截断的ADAMTS13在高剪切速率下对VWF的剪切活性降低。c端结构域的作用可能在血栓形成前变得越来越重要。（血液。2009;113:5323-5329）
ADAMTS13 is a multidomain protease that limits platelet thrombogenesis through the cleavage of von Willebrand factor (VWF). We previously identified 2 types of mouse Adamts13 gene: the 129/Sv-strain Adamts13 gene encodes the long-form ADAMTS13 having the same domains as human ADAMTS13, whereas the C57BL/6-strain Adamts13 gene encodes the short-form ADAMTS13 lacking the distal C-terminal domains. To assess the physiologic significance of the distal C-terminal domains of ADAMTS13, we generated and analyzed 129/Sv-genetic background congenic mice (Adamts13(S/S)) that carry the short-form ADAMTS13. Similar to wild-type 129/Sv mice (Adamts13(L/L)), Adamts13S/S did not have ultralarge VWF multimers in plasma, in contrast to 129/Sv-genetic background ADAMTS13-deficient mice (Adamts13(-/-)). However, in vitro thrombogenesis under flow at a shear rate of 5000 s(-1) was accelerated in Adamts13(S/S) compared with Adamts13(L/L). Both in vivo thrombus formation in ferric chloride-injured arterioles and thrombocytopenia induced by collagen plus epinephrine challenge were more dramatic in Adamts13(S/S) than in Adamts13(L/L) but less than in Adamts13(-/-). These results suggested that the C-terminally truncated ADAMTS13 exhibited decreased activity in the cleavage of VWF under high shear rate. Role of the C-terminal domains may become increasingly important under prothrombotic conditions. (Blood. 2009; 113: 5323-5329)