Endothelial glutathione-S-transferase A4-4 protects against oxidative stress and modulates iNOS expression through NF-kappaB translocation.
Our recent work in endothelial 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)-kappaB 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-kappaB mediated gene expression, but conflicting results on 4-HNE's effect on NF-kappaB have been reported. We compared the effect of 4-HNE on iNOS and the NF-kappaB pathway in control mouse pancreatic islet endothelial (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)-kappaB (p65) translocation in comparison with wild-type or vector-transfected cells. Immunohistochemical studies of early human plaques showed lower 4-HNE content and upregulation of iNOS, which we take to indicate that GSTA4-4 induction acts as an enzymatic defense against high levels of 4-HNE, since 4-HNE accumulated in more advanced plaques, when detoxification and exocytotic mechanisms are likely to be overwhelmed. These studies suggest that GSTA4-4 may play an important defensive role against atherogenesis through detoxification of 4-HNE and upregulation of iNOS.
Yang
Yongzhen
Y
Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Yang
Yusong
Y
Xu
Ya
Y
Lick
Scott D
SD
Awasthi
Yogesh C
YC
Boor
Paul J
PJ
D050197:Atherosclerosis / Q000201:enzymology / Q000473:pathology; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D016895:Culture Media, Serum-Free; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D042783:Endothelial Cells / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D005982:Glutathione Transferase / Q000494:pharmacology*; D006801:Humans; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species; D014162:Transfection; D014178:Translocation, Genetic / Q000502:physiology*
D016895:Culture Media, Serum-Free; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase