High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro
High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro
复制标题
DOI：
10.1016/j.jdiacomp.2006.02.001
复制
发表时间：
2007-01-01
影响因子：
3
通讯作者：
Hashimoto, Kozo
中科院分区：
文献类型：
--
作者：
Iwasaki, Yasumasa;Kambayashi, Machiko;Hashimoto, Kozo
糖尿病常常与凝血障碍如冠心病和中风有关。我们的目的是阐明高血糖导致促凝血状态的分子机制。 HuH7人肝细胞单独用高葡萄糖或与促炎细胞因子联合处理，并检查对介导急性期和凝血相关基因表达的转录因子核因子κ-B（NF-κB）活性的影响。结果表明，在存在胰岛素的情况下，将培养基葡萄糖浓度从 3 mM 增加至 24 mM 可使 NF-κ B-荧光素酶活性显着增强 40%。该效果是启动子特异性的，并且不能通过与 L-葡萄糖相当的高渗透压来模拟。促炎细胞因子如白细胞介素 1 和肿瘤坏死因子 α (TNF-α) 也会刺激 NF-κ B 依赖性转录，并在高血糖下显示出累加效应。在急性期或凝血/纤维蛋白溶解相关基因启动子（例如纤维蛋白原或纤溶酶原激活剂抑制剂-1）上也获得了类似的效果，所有这些启动子都显示出具有 NF-κ B 介导的转录。最后，用抗氧化剂 PDTC 预处理细胞完全消除了高葡萄糖的影响，并显着减弱了 TNF-α 的影响，表明活性氧的参与。这些结果表明（1）高葡萄糖和促炎性细胞因子以累加方式对 NF-κ B 介导的转录产生积极影响，并增强凝血相关基因表达；（2）这些影响至少部分是通过氧化应激的产生介导的，并且可能是糖尿病、高胰岛素血症、糖尿病等代谢综合征中血栓性疾病高发的原因。 肥胖和/或炎症。 (c) 2007 Elsevier Inc. 保留所有权利。
Diabetes mellitus is frequently associated with coagulation disorders such as coronary heart disease and stroke. We aimed to clarify the molecular mechanism whereby hyperglycemia causes the procoagulant state. HuH7 human hepatocyte cells were treated with high glucose alone or in combination with proinflammatory cytokines, and the effects on the activity of the transcription factor nuclear factor kappa-B (NF-kappa B), which mediates the expression of acute-phase and coagulation-related genes, were examined. The results showed that increasing the medium glucose concentration from 3 to 24 mM significantly enhanced NF-kappa B-luciferase activity by 40% in the presence of insulin. The effect was promoter specific and not mimicked by comparable hyperosmolality with L-glucose. Proinflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha (TNF-alpha) also stimulated NF-kappa B-dependent transcription and showed an additive effect with high glucose. Similar effects were obtained on acute-phase or coagulation/fibrinolysis-related gene promoters such as fibrinogen or plasminogen activator inhibitor-1, all of which are shown to have NF-kappa B-mediated transcription. Finally, pretreatment of the cells with an antioxidant PDTC completely abolished the effect of high glucose and markedly attenuated that of TNF-alpha, suggesting the involvement of reactive oxygen species. These results suggest that (1) high glucose as well as proinflammatory cytokines have positive effects on NF-kappa B-mediated transcription in an additive manner and enhance coagulation-related gene expression and (2) the effects are mediated, at least partly, by the generation of oxidative stress and may be responsible for the high prevalence of thrombotic disorders in the metabolic syndrome with diabetes, hyperinsulinemia, obesity, and/or inflammation. (c) 2007 Elsevier Inc. All rights reserved.