Endothelial glutathione-S-transferase A4-4 protects against oxidative stress and modulates iNOS expression through NF-{kappa}B translocation
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, 77555 (United States)
- Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas, 77555 (United States)
- Department of Human Biological Chemistry and Surgery, University of Texas Medical Branch, Galveston, Texas, 77555 (United States)
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)-{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 iNOS and the NF-{kappa}B 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)-{kappa}B (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.
- OSTI ID:
- 21140893
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 230, Issue 2; Other Information: DOI: 10.1016/j.taap.2008.03.018; PII: S0041-008X(08)00139-7; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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