title: Arsenite enhances tumor necrosis factor-alpha-induced expression of vascular cell adhesion molecule-1.
abstract: Epidemiological studies demonstrated a high association of vascular diseases with arsenite exposure. We hypothesize that arsenite potentiates the effect of proinflammatory cytokines on vascular endothelial cells, and hence contributes to atherosclerosis. In this study, we investigated the effect of arsenite and its induction of glutathione (GSH) on vascular cell adhesion molecule-1 (VCAM-1) protein expression in human umbilical vein endothelial cells (HUVECs) in response to tumor necrosis factor-alpha (TNF-alpha), a typical proinflammatory cytokine. Our study demonstrated that arsenite pretreatment potentiated the TNF-alpha-induced VCAM-1 expression with up-regulations of both activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB). To elucidate the role of GSH in regulation of AP-1, NF-kappaB, and VCAM-1 expression, we employed l-buthionine (S,R)-sulfoximine (BSO), a specific gamma-glutamylcysteine synthetase (gamma-GCS) inhibitor, to block intracellular GSH synthesis. Our investigation revealed that, by depleting GSH, arsenite attenuated the TNF-alpha-induced VCAM-1 expression as well as a potentiation of AP-1 and an attenuation of NF-kappaB activations by TNF-alpha. Moreover, we found that depletion of GSH would also attenuate the TNF-alpha-induced VCAM-1 expression with a down-regulation of the TNF-alpha-induced NF-kappaB activation and without significant effect on AP-1. On the other hand, the TNF-alpha-induced VCAM-1 expression could be completely abolished by inhibition of AP-1 or NF-kappaB activity, suggesting that activation of both AP-1 and NF-kappaB was necessary for VCAM-1 expression. In summary, we demonstrate that arsenite enhances the TNF-alpha-induced VCAM-1 expression in HUVECs via regulation of AP-1 and NF-kappaB activities in a GSH-sensitive manner. Our present study suggested a potential mechanism for arsenite in the induction of vascular inflammation and vascular diseases via modulating the actions of proinflammatory cytokines.
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan, ROC. tctsou@nhri.org.tw
authors.forename: Tsui-Chun
authors.initials: TC
authors.lastname: Tsou
authors.forename: Szu Ching
authors.initials: SC
authors.lastname: Yeh
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
authors.forename: Feng-Yuan
authors.initials: FY
authors.lastname: Tsai
authors.forename: How-Ran
authors.initials: HR
authors.lastname: Chao
authors.forename: Louis W
authors.initials: LW
authors.lastname: Chang
mesh_terms: D018053:Arsenites / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
chemical_list: D018053:Arsenites; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D019328:Buthionine Sulfoximine; D008156:Luciferases; D005978:Glutathione; C015001:arsenite