Decreased platelet inhibition by nitric oxide in two brothers with a history of arterial thrombosis
Decreased platelet inhibition by nitric oxide in two brothers with a history of arterial thrombosis
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DOI：
10.1172/jci118522
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发表时间：
1996-02-15
影响因子：
15.9
通讯作者：
Michelson, AD
中科院分区：
文献类型：
--
作者：
Freedman, JE;Loscalzo, J;Michelson, AD
高活性氧会迅速灭活一氧化氮 (NO)，一氧化氮是一种抑制血小板活化的内皮产物。我们在患有脑血栓疾病的两兄弟中研究了一氧化氮对血小板的抑制作用。通过全血血小板聚集度测定和 P-选择素血小板表面表达的流式细胞术分析确定，这两个孩子都患有高反应性血小板。混合实验表明，患者的血小板在对照血浆中表现正常；然而，悬浮在患者血浆中的对照血小板不受NO抑制。通过流式细胞术测定，在任一患者的血浆存在的情况下，前列环素对凝血酶诱导的血小板表面P-选择素的表达有正常的抑制作用，但NO没有抑制作用。使用东莨菪素测定，我们测量到一名患者血浆 H2O2 生成量增加了 2.7 倍，另一名患者血浆 H2O2 生成量增加了 3.4 倍，两者均与对照血浆相比。与对照血浆相比，患者血浆中的谷胱甘肽过氧化物酶（GSH-Px）活性降低。添加外源性 GSH-Px 导致 NO 对血小板的抑制作用恢复。这些数据表明，在这些患者的血浆中，活性氧代谢受损会降低一氧化氮的生物利用度并损害正常的血小板抑制机制。这些发现表明，活性氧增加或抗氧化防御受损所产生的一氧化氮介导的血小板抑制作用减弱可能会导致人类血栓性疾病。
Highly reactive oxygen species rapidly inactivate nitric oxide (NO), an endothelial product which inhibits platelet activation. We studied platelet inhibition by NO in two brothers with a cerebral thrombotic disorder. Both children had hyperreactive platelets, as determined by whole blood platelet aggregometry and flow cytometric analysis of the platelet surface expression of P-selectin. Mixing experiments showed that the patients' platelets behaved normally in control plasma; however, control platelets suspended in patient plasma were not inhibited by NO. As determined by flow cytometry, in the presence of plasma from either patient there was normal inhibition of the thrombin-induced expression of platelet surface P-selectin by prostacyclin, but not NO. Using a scopoletin assay, we measured a 2.7-fold increase in plasma H2O2 generation in one patient and a 3.4-fold increase in the second patient, both compared with control plasma. Glutathione peroxidase (GSH-Px) activity was decreased in the patients' plasmas compared with control plasma. The addition of exogenous GSH-Px led to restoration of platelet inhibition by NO. These data show that, in these patients' plasmas, impaired metabolism of reactive oxygen species reduces the bioavailability of NO and impairs normal platelet inhibitory mechanisms. These findings suggest that attenuated NO-mediated platelet inhibition produced by increased reactive oxygen species or impaired antioxidant defense may cause a thrombotic disorder in humans.