Adenosine diphosphate (ADP)-induced thromboxane A2 generation in human platelets requires coordinated signaling through integrin αIIBβ3 and ADP receptors
Adenosine diphosphate (ADP)-induced thromboxane A2 generation in human platelets requires coordinated signaling through integrin αIIBβ3 and ADP receptors
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DOI：
10.1182/blood.v99.1.193
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发表时间：
2002-01-01
期刊：
影响因子：
20.3
通讯作者：
Kunapuli, SP
中科院分区：
文献类型：
--
作者：
Jin, JG;Quinton, TM;Kunapuli, SP
二磷酸腺苷（Adenosine diphosphate， ADP）是一种血小板激动剂，通过作用于P2Y1、P2Y12和P2X1受体，引起血小板形状改变和聚集，并产生另一种血小板激动剂血栓素a(2)。现在有报道称，P2Y12受体选择性拮抗剂2-丙基硫代-d - γ -二氯甲基腺苷t -三磷酸（AR-C67085）和P2Y1受体选择性拮抗剂腺苷-2′-磷酸-5′-磷酸（A2P5P）以浓度依赖性的方式抑制adp诱导的血栓素a(2)的生成，这表明P2Y12和P2Y1受体的共激活对这一事件至关重要。SC49992，一种纤维蛋白原受体拮抗剂，以浓度依赖的方式阻断adp诱导的血小板聚集和凝血素a(2)的产生。同样，P2受体拮抗剂或SC49992阻断adp诱导的花生四烯酸释放。SC49992能阻断花生四烯酸诱导的血小板聚集，但不能抑制花生四烯酸诱导的血栓素A(2)的生成。因此，adp诱导的花生四烯酸释放，而不是随后转化为血栓素A(2)，需要通过纤维蛋白原受体的外向内信号传导。配体诱导结合位点-6 （LIBS6）抗体Fab片段诱导整合素α (IIb) β上的纤维蛋白原结合位点(3)，引起血小板聚集和血栓素a(2)的产生。磷酸肌肽3-激酶、Syk、Src激酶或蛋白酪氨酸磷酸酶抑制剂抑制血小板聚集，但不抑制血栓素A(2)的生成，表明这些信号分子在磷脂酶A(2)的激活中没有显著作用。在P2受体拮抗剂A2P5P或AR-C67085存在的情况下，LIBS6不能产生血栓素A(2)，这表明通过ADP受体的内向外信号传导是这一事件的必要条件。综上所述，纤维蛋白原受体的外向内信号和P2Y1和P2Y12受体的内向外信号都是磷脂酶A(2)激活所必需的，从而导致花生四烯酸的释放和血栓素A(2)的产生。
Adenosine diphosphate (ADP) is a platelet agonist that causes platelet shape change and aggregation as well as generation of thromboxane A(2), another platelet agonist, through its effects on P2Y1, P2Y12, and P2X1 receptors. it is now reported that both 2-propylthio-D-beta gamma -dichloromethylene adenosine T-triphosphate (AR-C67085), a P2Y12 receptor-selective antagonist, and adenosine-2'-phosphate-5'-phosphate (A2P5P), a P2Y1 receptor-selective antagonist, inhibited ADP-induced thromboxane A(2) generation in a concentration-dependent manner, indicating that coactivation of the P2Y12 and P2Y1 receptors is essential for this event. SC49992, a fibrinogen receptor antagonist, blocked ADP-induced platelet aggregation and thromboxane A(2) production in a concentration-dependent manner. Similarly, P2 receptor antagonists or SC49992 blocked ADP-Induced arachidonic acid liberation. Whereas SC49992 blocked arachidonic acid-induced platelet aggregation, it failed to inhibit thromboxane A(2) generation induced by arachidonic acid. Thus, ADP-induced arachidonic acid liberation, but not subsequent conversion to thromboxane A(2), requires outside-in signaling through the fibrinogen receptor. The Fab fragment of ligand-induced binding site-6 (LIBS6) antibody, which induces a fibrinogen-binding site on the integrin alpha (IIb)beta (3), caused both platelet aggregation and thromboxane A(2) generation. Inhibitors of phosphoinositide 3-kinase, Syk, Src kinases, or protein tyrosine phosphatases inhibited platelet aggregation but not thromboxane A(2) generation, indicating that these signaling molecules have no significant role in phospholipase A(2) activation. In the presence of P2 receptor antagonists A2P5P or AR-C67085, LIBS6 failed to generate thromboxane A(2), suggesting that inside-out signaling through ADP receptors is necessary for this event. It was concluded that both outside-in signaling from the fibrinogen receptor and inside-out signaling from the P2Y1 and P2Y12 receptors are necessary for phospholipase A(2) activation, resulting in arachidonic acid liberation and thromboxane A(2) generation.