Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A
Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A
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DOI：
10.1182/blood-2004-10-4092
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发表时间：
2005-08-01
期刊：
影响因子：
20.3
通讯作者：
Kanakura, Y
中科院分区：
文献类型：
--
作者：
Kashiwagi, H;Shiraga, M;Kanakura, Y
Semaphorin 3A (Sema3A) 是一种分泌型二硫键结合同型二聚体分子，可诱导生长锥塌陷并排斥神经系统中的轴突生长。最近，已经证明Sema3A是由内皮细胞产生并以自分泌方式抑制整合素功能。在这项研究中，我们通过使用 2 种不同的人类 Sema3A 嵌合蛋白研究了 Sema3A 对血小板功能的影响。我们检测到血小板中功能性 Sema3A 受体的表达以及 Sema3A 与血小板的紧密依赖性和可饱和结合。 Sema3A剂量依赖性地抑制所有所检查的激动剂对整联蛋白αIIbβ3的激活，包括二磷酸腺苷(ADP)、凝血酶、惊厥素、佛波醇12-肉豆蔻酸酯13-乙酸酯和A23187。 Sema3A 不仅抑制凝血酶或胶原诱导的血小板聚集，还抑制血小板在固定纤维蛋白原上的粘附和扩散。此外，Sema3A 损害了玻璃盖玻片上不依赖于 α 11b β 3 的铺展和不依赖于聚集的颗粒分泌。 Sema3A 抑制激动剂诱导的丝状作用 (F-肌动蛋白) 含量升高、丝切蛋白磷酸化和 Racl 激活。相反，Sema3A 不影响环核苷酸的水平或激动剂诱导的细胞内 Ca2+ 浓度的增加。因此，Sema3A 对血小板功能的广泛抑制似乎至少部分是通过破坏激动剂诱导的 Rac1 依赖性肌动蛋白重排来介导的。
Semaphorin 3A (Sema3A) is a secreted disulfide-bound homodimeric molecule that induces growth cone collapse and repulsion of axon growth in the nervous system. Recently, it has been demonstrated that Sema3A is produced by endothelial cells and inhibits integrin function in an autocrine fashion. In this study, we investigated the effects of Sema3A on platelet function by using 2 distinct human Sema3A chimera proteins. We detected expression of functional Sema3A receptors in platelets and close-dependent and saturable binding of Sema3A to platelets. Sema3A dose-dependently inhibited activation of integrin alpha llb beta 3 by all agonists examined including adenosine diphosphate (ADP), thrombin, convulxin, phorbol 12-myristate 13-acetate, and A23187. Sema3A inhibited not only platelet aggregation induced by thrombin or collagen but also platelet adhesion and spreading on immobilized fibrinogen. Moreover, Sema3A impaired alpha llb beta 3-independent spreading on glass coverslips and aggregation-independent granular secretion. Sema3A inhibited agonist-induced elevation of filamentous action (F-actin) contents, phosphorylation of cofilin, and Racl activation. In contrast, Sema3A did not affect the levels of cyclic nucleotides or agonist-Induced increase of intracellular Ca2+ concentrations. Thus, the extensive inhibition of platelet function by Sema3A appears to be mediated, at least in part, through impairment of agonist-induced Rac1-dependent actin rearrangement.