G13 is an essential mediator of platelet activation in hemostasis and thrombosis
G13 is an essential mediator of platelet activation in hemostasis and thrombosis
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DOI：
10.1038/nm943
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发表时间：
2003-11-01
期刊：
影响因子：
82.9
通讯作者：
Offermanns, S
中科院分区：
文献类型：
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作者：
Moers, A;Nieswandt, B;Offermanns, S
血管损伤部位的血小板激活对于初次止血是必不可少的，但也是导致心肌梗死或中风的动脉血栓形成的基础(1，2)。血小板激活剂如二磷酸腺苷、凝血酶或血栓素A(2)(TXA(2))激活与异三聚体G蛋白(1，3)偶联的受体。通过这些受体激活血小板涉及通过G(Q)、G(I)和G(Z)传递信号(参考文献)。4-6)。然而，G(12)和G(13)的作用和相对重要性尚不清楚，G(12)和G(13)由各种血小板刺激(7-9)激活。在这里，我们显示缺乏Galpha(13)，而不是Galpha(12)，在体外严重降低凝血酶、TXA(2)和胶原诱导血小板形状变化和聚集的效力。这些缺陷伴随着RhoA活性降低和在体外高切应力下不能形成稳定的血小板血栓。在体内，血小板中的Galpha(13)缺乏导致一次止血和对动脉血栓的完全保护的严重缺陷。我们得出结论，G(13)介导的信号过程是正常止血和血栓形成所必需的，并可能成为抗血小板药物的新靶点。
Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke(1,2). Platelet activators such as adenosine diphosphate, thrombin or thromboxane A(2) (TXA(2)) activate receptors that are coupled to heterotrimeric G proteins(1,3). Activation of platelets through these receptors involves signaling through G(q), G(i) and G(z) (refs. 4- 6). However, the role and relative importance of G(12) and G(13), which are activated by various platelet stimuli(7-9), are unclear. Here we show that lack of Galpha(13), but not Galpha(12), severely reduced the potency of thrombin, TXA(2) and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Galpha(13) deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G(13)-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.