Glutathione Peroxidase-1 Deficiency Augments Proinflammatory Cytokine-induced Redox Signaling and Human Endothelial Cell Activation
Glutathione Peroxidase-1 Deficiency Augments Proinflammatory Cytokine-induced Redox Signaling and Human Endothelial Cell Activation
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DOI：
10.1074/jbc.m110.205708
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发表时间：
2011-10-14
影响因子：
4.8
通讯作者：
Handy, Diane E.
中科院分区：
文献类型：
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作者：
Lubos, Edith;Kelly, Neil J.;Handy, Diane E.
谷胱甘肽过氧化物酶-1 (GPx-1) 是一种重要的抗氧化酶，其缺乏会促进动脉粥样硬化形成。因此，我们研究了 GPx-1 缺乏增强内皮细胞活化和炎症的机制。在人微血管内皮细胞中，我们发现 GPx-1 缺乏会通过涉及 NF kappa B 的氧化还原依赖性机制增强细胞间粘附分子-1 (ICAM-1) 和血管细胞粘附分子-1 (VCAM-1) 的表达。抑制 GPx-1 会增强 TNF-α 诱导的 ROS 产生和 ICAM-1 表达，而 GPx-1 的过度表达会减弱这些 TNF-α 介导的反应。 GPx-1 缺乏会延长 TNF-α 诱导的 I kappa B α 降解以及 ERK1/2 和 JNK 的激活。 JNK 或 NF kappa B 抑制减弱了 GPx-1 缺陷细胞和对照细胞中 TNF-α 对 ICAM-1 和 VCAM-1 表达的诱导，而 ERK1/2 抑制仅减弱了 VCAM-1 表达。为了进一步分析参与 GPx-1 介导的 TNF-α 诱导的 ROS 保护的信号通路，我们对在存在和不存在 GPx-1 的情况下用 TNF-α 处理的人微血管内皮细胞进行了微阵列分析。在表达显着变化的基因中，编码 MAPK 信号传导拮抗剂的双特异性磷酸酶 4 (DUSP4) 通过 GPx-1 抑制而下调。靶向 DUSP4 敲低增强了 TNF-α 介导的 ERK1/2 通路激活，并导致粘附分子表达增加，表明 GPx-1 缺陷可能部分通过调节 DUSP4 来增强 TNF-α 介导的事件。
Glutathione peroxidase-1 (GPx-1) is a crucial antioxidant enzyme, the deficiency of which promotes atherogenesis. Accordingly, we examined the mechanisms by which GPx-1 deficiency enhances endothelial cell activation and inflammation. In human microvascular endothelial cells, we found that GPx-1 deficiency augments intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression by redox-dependent mechanisms that involve NF kappa B. Suppression of GPx-1 enhanced TNF-alpha-induced ROS production and ICAM-1 expression, whereas overexpression of GPx-1 attenuated these TNF-alpha-mediated responses. GPx-1 deficiency prolonged TNF-alpha-induced I kappa B alpha degradation and activation of ERK1/2 and JNK. JNK or NF kappa B inhibition attenuated TNF-alpha induction of ICAM-1 and VCAM-1 expression in GPx-1-deficient and control cells, whereas ERK1/2 inhibition attenuated only VCAM-1 expression. To analyze further signaling pathways involved in GPx-1-mediated protection from TNF-alpha-induced ROS, we performed microarray analysis of human microvascular endothelial cells treated with TNF-alpha in the presence and absence of GPx-1. Among the genes whose expression changed significantly, dual specificity phosphatase 4 (DUSP4), encoding an antagonist of MAPK signaling, was down-regulated by GPx-1 suppression. Targeted DUSP4 knockdown enhanced TNF-alpha-mediated ERK1/2 pathway activation and resulted in increased adhesion molecule expression, indicating that GPx-1 deficiency may augment TNF-alpha-mediated events, in part, by regulating DUSP4.