Insulin induces the release of vasodilator compounds from platelets by a nitric oxide-G kinase-VAMP-3-dependent pathway
Insulin induces the release of vasodilator compounds from platelets by a nitric oxide-G kinase-VAMP-3-dependent pathway
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DOI：
10.1084/jem.20030694
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发表时间：
2004-02-02
影响因子：
15.3
通讯作者：
Fleming, I
中科院分区：
文献类型：
--
作者：
Randriamboavonjy, V;Schrader, J;Fleming, I
胰岛素诱导的血管舒张对一氧化氮合酶（NOS）抑制剂敏感。然而，胰岛素不能放松离体动脉或激活内皮细胞中的内皮NOS。由于胰岛素可以增强血小板内皮NOS活性，我们确定胰岛素诱导的血管舒张是否可以归因于no依赖的血小板介导过程。胰岛素不能使猪冠状动脉内皮完整环松弛。来自胰岛素刺激的人血小板的上清诱导完全松弛，通过将血小板与NOS抑制剂、可溶性guanyyl环化酶抑制剂NS 2028或G激酶抑制剂KT 5823预孵育可以阻止完全松弛，并通过腺苷a （2A）受体拮抗剂消除。胰岛素诱导血小板致密颗粒以no依赖的方式释放三磷酸腺苷（ATP）、腺苷和血清素。使用胰岛素刺激的内皮细胞NOS-/-小鼠的血小板未检测到这种反应，尽管NO供体诱导ATP释放。胰岛素诱导的血小板ATP释放与syntaxin 2与囊泡相关膜蛋白3的关联相关，但与α (IIb) β(3)整合素的激活无关。因此，胰岛素通过NO-G激酶依赖的信号级联从人血小板中诱导血管活性浓度的ATP和腺苷的释放。致密颗粒分泌的机制涉及G激酶依赖的syntaxin 2与囊泡相关膜蛋白3的结合。
Insulin-induced vasodilatation is sensitive to nitric oxide (NO) synthase (NOS) inhibitors. However, insulin is unable to relax isolated arteries or to activate endothelial NOS in endothelial cells. Since insulin can enhance platelet endothelial NOS activity, we determined whether insulin-induced vasodilatation can be attributed to a NO-dependent, platelet-mediated process.Insulin failed to relax endothelium-intact rings of porcine coronary artery. The supernatant from insulin-stimulated human platelets induced complete relaxation, which was prevented by preincubation of platelets with a NOS inhibitor, the soluble guanylyl cyclase inhibitor, NS 2028, or the G kinase inhibitor, KT 5823, and was abolished by an adenosine A(2A) receptor antagonist. Insulin induced the release of adenosine trisphosphate (ATP), adenosine, and serotonin from platelet-dense granules in a NO-dependent manner. This response was not detected using insulin-stimulated platelets from endothelial NOS-/- mice, although a NO donor elicited ATP release. Insulin-induced ATP release from human platelets correlated with the association of syntaxin 2 with the vesicle-associated membrane protein 3 but was not associated with the activation of alpha(IIb)beta(3) integrin. Thus, insulin elicits the release of vasoactive concentrations of ATP and adenosine from human platelets via a NO-G kinase-dependent signaling cascade. The mechanism of dense granule secretion involves the G kinase-dependent association of syntaxin 2 with vesicle-associated membrane protein 3.