Glutathione peroxidase-1 deficiency augments proinflammatory cytokine-induced redox signaling and human endothelial cell activation.

ABSTRACT: 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?B. Suppression of GPx-1 enhanced TNF-?-induced ROS production and ICAM-1 expression, whereas overexpression of GPx-1 attenuated these TNF-?-mediated responses. GPx-1 deficiency prolonged TNF-?-induced I?B? degradation and activation of ERK1/2 and JNK. JNK or NF?B inhibition attenuated TNF-? 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-?-induced ROS, we performed microarray analysis of human microvascular endothelial cells treated with TNF-? 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-?-mediated ERK1/2 pathway activation and resulted in increased adhesion molecule expression, indicating that GPx-1 deficiency may augment TNF-?-mediated events, in part, by regulating DUSP4.

SUBMITTER: Lubos E 

PROVIDER: S-EPMC3195617 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature