Cellular adaptive response to glutathione depletion modulates endothelial dysfunction triggered by TNF-alpha: involvement of Nrf2/ARE pathway

Cells are continously exposed to the deleterious consequences of reactive oxigen species generated endogenously and exogenously. Cells have developed multiple stress adaptive response, including the system regulated by the transcription factor Nrf2 that modulates a set of cytoprotective genes. Up today there are few data supporting the atheroprotective and anti-inflammatory activity of Nrf2 pathway in endothelial cells. Thus to test this hypothesis we have investigated if some changes in the intracellular redox status, such as those related to endogenous antioxidants depletion, might be able to alter the response to the inflammatory cytokine TNF-α in cultured human endothelial cells through the activation of the Nrf2 pathway. In this study, we revealed that an oxidative intracellular status by GSH depletion is able to induce a cellular adaptive response. Interestingly we demonstrated that, in our experimental conditions, activation of Nrf2 pathway is able to reduce endothelial dysfunction by decreasing NF-kB nuclear translocation and adhesion molecules gene expression in HUVECs. Furthermore, we confirmed that Nrf2 nuclear translocation activated by GSH depletion is dependent on extracellular signal-regulated kinases 1/2 phosphorylation. In conclusion we showed that the coordinate induction of endogenous cytoprotective proteins through activation of the Nrf2 pathway might serve as a new therapeutic approach for prevention or treatment of endothelial dysfunction.