Endothelial glutathione-S-transferase A4-4 protects against oxidative stress and modulates NOS expression through NF-κB translocation

our recent work in enclothelial cells and human atherosclerotic plaque showed that overexpression of glutathione-S-tranferases (GSTs) in endothelium protects against oxidative damage from aldehydes such as 4-HNE. Nuclear factor (NF)-kappa B plays a crucial role during inflammation and immune responses by regulating the expression of inducible genes such as inducible nitric oxide synthase (iNOS). 4-HNE induces apoptosis and affects NF-kappa B mediated gene expression, but conflicting results on 4-HNE's effect on NF-kappa B have been reported. We compared the effect of 4-HNE on MOS and the NF-kappa B pathway in control mouse pancreatic islet enclothelial (MS1) cells and those transfected with mGSTA4, a alpha-class GST with highest activity toward 4-HNE. When treated with 4-HNE, mGSTA4-transfected cells showed significant upregulation of iNOS and nitric oxide (NO) through (NF)-kappa B (p65) translocation in comparison with wild-type or vector-transfected cells. firnmunohistochemical studies of early human plaques showed lower 4-HNE content and upregulation of iNOS, which we take to indicate that GSTA44 induction acts as an enzymatic defense against high levels of4HNE, since 4-HNE accumulated in more advanced plaques, when cletoxification and exocytotic mechanisms are likely to be overwhelmed. These studies suggest that GSTA44 may play an important defensive role against atherogenesis through cletoxification of 4-HNE and upregulation of iNOS. (c) 2008 Elsevier Inc. All rights reserved.