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

Yongzhen Yang, Yusong Yang, Ya Xu, Scott D. Lick, Yogesh C. Awasthi, Paul J. Boor

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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)-κB 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-κB mediated gene expression, but conflicting results on 4-HNE's effect on NF-κB have been reported. We compared the effect of 4-HNE on iNOS and the NF-κB pathway in control mouse pancreatic islet endothelial (MS1) cells and those transfected with mGSTA4, a α-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)-κB (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.

Original languageEnglish (US)
Pages (from-to)187-196
Number of pages10
JournalToxicology and Applied Pharmacology
Volume230
Issue number2
DOIs
StatePublished - Jul 15 2008

Keywords

  • Atherosclerosis
  • Glutathione-S-transferase
  • Inducible nitric oxide synthase
  • NF-κB
  • Nitric oxide

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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