title: 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 NFκB. Suppression of GPx-1 enhanced TNF-α-induced ROS production and ICAM-1 expression, whereas overexpression of GPx-1 attenuated these TNF-α-mediated responses. GPx-1 deficiency prolonged TNF-α-induced IκBα degradation and activation of ERK1/2 and JNK. JNK or NFκB inhibition attenuated TNF-α 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-α-induced ROS, we performed microarray analysis of human microvascular endothelial cells treated with TNF-α 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-α-mediated ERK1/2 pathway activation and resulted in increased adhesion molecule expression, indicating that GPx-1 deficiency may augment TNF-α-mediated events, in part, by regulating DUSP4.
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Edith
authors.initials: E
authors.lastname: Lubos
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Kelly
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Oldebeken
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115. Electronic address: dhandy@rics.bwh.harvard.edu.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Handy
mesh_terms: D002478:Cells, Cultured; D054637:Dual-Specificity Phosphatases / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000201:enzymology*; D004789:Enzyme Activation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D055785:Gene Knockdown Techniques; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000096:biosynthesis / Q000235:genetics; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
chemical_list: D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D005979:Glutathione Peroxidase; D051550:I-kappa B Kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human