Direct interaction of kindlin-3 with integrin αIIbβ3 in platelets is required for supporting arterial thrombosis in mice.
Direct interaction of kindlin-3 with integrin αIIbβ3 in platelets is required for supporting arterial thrombosis in mice.
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DOI：
10.1161/atvbaha.114.303851
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Ma YQ
中科院分区：
文献类型：
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作者：
Xu Z;Chen X;Zhi H;Gao J;Bialkowska K;Byzova TV;Pluskota E;White GC 2nd;Liu J;Plow EF;Ma YQ
Kindlin-3是血小板中整合素功能的关键支持者。患者中Kindlin-3蛋白表达的缺乏损害了整合素αIIbβ3介导的血小板聚集。尽管kindlin-3已被归类为整合素结合伴侣，但尚未确定kindlin-3与血小板中整合素αIIbβ3直接相互作用的功能意义。在这里，我们评估了kindlin-3与血小板中整合素αIIbβ3的结合在支持整合素αIIbβ3介导的血小板功能中的意义。我们产生了一种表达kindlin-3突变体的kindlin-3基因敲入（K3 KI）小鼠，该突变体携带整合素相互作用缺陷型取代。K3 KI小鼠能正常存活，血小板上整合素αIIbβ3的表达与野生型小鼠相似。功能分析显示，K3 KI小鼠表现出血小板功能缺陷，包括整合素αIIbβ3活化受损、血小板铺展和血小板聚集受抑制、尾部出血时间延长以及缺乏血小板介导的凝块收缩。此外，从K3 KI小鼠抽取的全血显示出对体外血栓形成的抗性，因此，K3 KI小鼠受到保护，免于体内动脉血栓形成。这些观察结果表明，kindlin-3与整合素αIIbβ3的直接结合参与支持整合素αIIbβ3活化和血小板的整合素αIIbβ3依赖性反应，因此显著促进动脉血栓形成
Kindlin-3 is a critical supporter of integrin function in platelets. Lack of expression of kindlin-3 protein in patients impairs integrin αIIbβ3-mediated platelet aggregation. Although kindlin-3 has been categorized as an integrin-binding partner, the functional significance of the direct interaction of kindlin-3 with integrin αIIbβ3 in platelets has not been established. Here, we evaluated the significance of the binding of kindlin-3 to integrin αIIbβ3 in platelets in supporting integrin αIIbβ3-mediated platelet functions. We generated a strain of kindlin-3 knock-in (K3KI) mice that express a kindlin-3 mutant that carries an integrin-interaction defective substitution. K3KI mice could survive normally and express integrin αIIbβ3 on platelets similarly to their wild type counterparts. Functional analysis revealed that K3KI mice exhibited defective platelet function, including impaired integrin αIIbβ3 activation, suppressed platelet spreading and platelet aggregation, prolonged tail bleeding time, and absence of platelet-mediated clot retraction. In addition, whole blood drawn from K3KI mice showed resistance to in vitro thrombus formation and, as a consequence, K3KI mice were protected from in vivo arterial thrombosis. These observations demonstrate that the direct binding of kindlin-3 to integrin αIIbβ3 is involved in supporting integrin αIIbβ3 activation and integrin αIIbβ3-dependent responses of platelets and consequently contributes significantly to arterial thrombus formation