title: Cellular adaptive response to glutathione depletion modulates endothelial dysfunction triggered by TNF-α.
abstract: Several interrelated cellular signaling molecules are involved in modulating adaptive compensatory changes elicited by low exposures to toxins and other stressors. The most prominent example of signaling pathway typically involved in this adaptive stress response, is represented by the activation of a redox-sensitive gene regulatory network mediated by the NF-E2-related factor-2 (Nrf2) which is intimately involved in mediating the Antioxidant Responsive Element (ARE)-driven response to oxidative stress and xenobiotics. We investigated if Nrf2 pathway activation following intracellular glutathione depletion through buthionine sulfoximine (BSO) exposure, might be able to alter the response to TNF-α, a proinflammatory cytokine, in cultured human umbilical vein endothelial cells. Herein, we revealed that such a change in the cellular redox status is able to reduce TNF-α induced endothelial activation (as shown by a decreased gene expression of adhesion molecules) by activating an adaptive response mediated by an increased Nrf2 nuclear translocation and overexpression of the ARE genes HO-1 and NQO-1. Furthermore, we have demonstrated the involvement of ERK1/2 kinases in Nrf2 nuclear translocation activated by BSO-induced glutathione depletion. The coordinate induction of endogenous cytoprotective proteins through adaptive activation of Nrf2 pathway is a field of great interest for potential application in prevention and therapy of inflammatory diseases such as atherosclerosis.
authors.affiliation: Department Farmaco-Biologico, School of Pharmacy, University of Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Speciale
authors.forename: Sirajudheen
authors.initials: S
authors.lastname: Anwar
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ricciardi
authors.forename: Joselita
authors.initials: J
authors.lastname: Chirafisi
authors.forename: Antonella
authors.initials: A
authors.lastname: Saija
authors.forename: Francesco
authors.initials: F
authors.lastname: Cimino
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000032:analysis / Q000172:deficiency*; D061307:Human Umbilical Vein Endothelial Cells / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D015815:Cell Adhesion Molecules; D051267:NF-E2-Related Factor 2; D014409:Tumor Necrosis Factor-alpha; D019328:Buthionine Sulfoximine; D020929:Mitogen-Activated Protein Kinase Kinases; D005978:Glutathione