Cellular adaptive response to glutathione depletion modulates endothelial dysfunction triggered by TNF-α

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-, 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- 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.