Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases
Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases
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DOI：
10.1074/jbc.m301838200
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发表时间：
2003-08-15
影响因子：
4.8
通讯作者：
Du, XP
中科院分区：
文献类型：
--
作者：
Li, ZY;Zhang, GY;Du, XP
血栓素A（2）（TXA（2））介导的血小板分泌和聚集在血栓形成中是重要的。在这里，我们提出了一个新的发现，稳定的TXA 2类似物，U46619，诱导两波血小板分泌，每一个之前的血小板聚集的一个独特的波。血小板在第一波分泌过程中释放的ADP在增加血小板聚集的第一波中起主要作用。血小板分泌和聚集的第二波需要ADP分泌和聚集的第一波，并且被整合素抑制剂RGDS或P2 Y12受体拮抗剂阻断，表明需要整合素外向内信号和ADP激活的G（i）途径。U46619刺激Akt的磷酸肌醇3-激酶（PI 3 K）依赖性磷酸化，这是由ADP增强，但不需要整合素外向内信号。来自PI 3 K γ敲除小鼠或PI 3 K受体处理的血小板的血小板显示血小板分泌和聚集的第二波受损。然而，第二波血小板聚集恢复加入外源性ADP的PI 3 K γ缺陷或PI 3 K受体处理的血小板。因此，我们的数据表明，PI 3 K，连同整合素外向内信号，在诱导血小板分泌的第二波，这导致不可逆的血小板聚集的第二波中发挥核心作用。
Thromboxane A(2) (TXA(2))-mediated platelet secretion and aggregation are important in thrombosis. Here, we present a novel finding that the stable TXA2 analogue, U46619, induces two waves of platelet secretion, each of which precedes a distinct wave of platelet aggregation. ADP released from platelets during the first wave of secretion played a major role in augmenting the first wave of platelet aggregation. The second wave of platelet secretion and aggregation required the first wave of both ADP secretion and aggregation and were blocked by either the integrin inhibitor RGDS or a P2Y12 receptor antagonist, indicating a requirement for both the integrin outside-in signal and ADP-activated G(i) pathway. U46619 stimulated phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of Akt, which was augmented by ADP but did not require integrin outside-in signaling. Platelets from PI3Kgamma knock-out mice or PI3K inhibitor-treated platelets showed an impaired second wave of platelet secretion and aggregation. However, the second wave of platelet aggregation was restored by addition of exogenous ADP to PI3Kgamma deficient or PI3K inhibitor-treated platelets. Thus, our data indicate that PI3K, together with the integrin outside-in signaling, play a central role in inducing the second wave of platelet secretion, which leads to the second wave of irreversible platelet aggregation.