Vascular Biology Center and Division of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School, 420 Delaware Street SE, University of Minnesota, Minneapolis, MN 55455, USA.
Am J Hematol. 2010 Jan;85(1):41-5. doi: 10.1002/ajh.21582.
Activation of the coagulation system is a characteristic feature of sickle cell anemia, which also includes clinical thrombosis. The sickle transgenic mouse abnormally expresses tissue factor (TF) on the pulmonary vein endothelium. Knowing that this aberrancy is stimulated by inflammation, we sought to determine whether nitric oxide (NO) contributes to regulation of endothelial TF expression in the sickle mouse model. We used the NY1DD sickle mouse, which exhibits a low-TF to high-TF phenotype switch on exposure to hypoxia/reoxygenation. Manipulations of NO biology, such as breathing NO or addition of arginine or L-NAME (N-nitro-L-arginine-methyl-ester) to the diet, caused significant modulations of TF expression. This was also seen in hBERK1 sickle mice, which have a different genetic background and already have high-TF even at ambient air. Study of NY1DD animals bred to overexpress endothelial nitric oxide synthase (eNOS; eNOS-Tg) or to have an eNOS knockout state (one eNOS(-/-) animal and several eNOS(+/-) animals) demonstrated that eNOS modulates endothelial TF expression in vivo by down-regulating it. Thus, the biodeficiency of NO characteristic of patients with sickle cell anemia may heighten risk for activation of the coagulation system.
凝血系统的激活是镰状细胞贫血的一个特征，其中还包括临床血栓形成。镰状转基因小鼠的肺静脉内皮细胞异常表达组织因子 (TF)。由于知道这种异常是由炎症刺激引起的，我们试图确定一氧化氮 (NO) 是否有助于调节镰状小鼠模型中内皮 TF 的表达。我们使用了 NY1DD 镰状小鼠，其在暴露于低氧/复氧时表现出低 TF 到高 TF 的表型转换。NO 生物学的操作，如呼吸 NO 或在饮食中添加精氨酸或 L-NAME（N-硝基-L-精氨酸甲酯），导致 TF 表达的显著调节。在 hBERK1 镰状小鼠中也观察到了这种情况，hBERK1 镰状小鼠具有不同的遗传背景，即使在环境空气中也已经具有高 TF。对过度表达内皮型一氧化氮合酶 (eNOS；eNOS-Tg)或具有 eNOS 敲除状态的 NY1DD 动物 (一只 eNOS(-/-)动物和几只 eNOS(+/-)动物)的研究表明，eNOS 通过下调来调节体内内皮 TF 的表达。因此，镰状细胞贫血患者中特征性的 NO 生物缺陷可能会增加凝血系统激活的风险。
