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

Toxicol Appl Pharmacol. 2008 Jul 15;230(2):187-96. doi: 10.1016/j.taap.2008.03.018. Epub 2008 Apr 7.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Atherosclerosis / enzymology
  • Atherosclerosis / pathology
  • Blotting, Western
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Culture Media, Serum-Free
  • Cytoplasm / metabolism
  • Cytoplasm / ultrastructure
  • Endothelial Cells / enzymology*
  • Enzyme Activation / physiology
  • Glutathione Transferase / pharmacology*
  • Humans
  • Microscopy, Confocal
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Nitric Oxide Synthase Type II / biosynthesis*
  • Nitric Oxide Synthase Type II / genetics
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species
  • Transfection
  • Translocation, Genetic / physiology*


  • Culture Media, Serum-Free
  • NF-kappa B
  • Reactive Oxygen Species
  • Nitric Oxide Synthase Type II
  • Glutathione Transferase
  • leukotriene-C4 synthase