Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 41, Pages 35407-35417Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.205708
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Funding
- National Institutes of Health [HL 58976, HL 61795, HV 28178, HL 81587, HL 48743]
- NHLBI
- Deutsche Forschungsgemeinschaft [LU 1452/1-1, LU 1452/2-1]
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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.
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