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 (HMVEC), 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¿B. Suppression of GPx-1 enhanced TNF-a-induced ROS production and ICAM-1 expression, whereas overexpression of GPx-1 attenuated these TNF-a-mediated responses. GPx-1 deficiency prolonged TNF-a-induced I¿Ba degradation and activation of ERK1/2 and JNK. JNK- or NF¿B-inhibition attenuated TNF-a 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-a-induced ROS, we performed microarray analysis of HMVEC treated with TNF-a in the presence and absence of GPx-1. Among the genes whose expression changed significantly, dual specificity phosphatase 4 (DUSP4), an antagonist of MAPK signaling, was downregulated by GPx-1 suppression. Targeted DUSP4 knockdown enhanced TNF-a-mediated ERK1/2 pathway activation and resulted in increased adhesion molecule expression, indicating that GPx-1 deficiency may augment TNF-a-mediated events, in part, by regulating DUSP4.

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