Role of glutathione redox cycle in TNF-α-mediated endothelial cell dysfunction

Michal Toborek, Steven W. Barger, Mark P. Mattson, Craig J. McClain, Bernhard Hennig

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Modulation of the glutathione redox cycle may influence tumor necrosis factor-α (TNF)-mediated disturbances of endothelial integrity. To test this hypothesis, normal endothelial cells or cells with either increased or decreased glutathione levels were exposed to 100 ng (500 U) TNF/ml. Increased glutathione levels were achieved by exposure to 0.2 mM N-acetyl-L-cysteine (NAC) and decreased glutathione levels by exposure to 25 μM buthionine sulfoximine (BSO). Several components of the glutathione redox cycle as well as markers of endothelial integrity, such as cytoplasmic free calcium and transendothelial albumin transfer, were measured in the treated cells. Exposure to TNF for 3 and 6 h decreased total glutathione levels, which was followed by an increase at later time points. Moreover, treatment with TNF resulted in an increase in the ratio of oxidized to reduced glutathione, intracellular free calcium, albumin transfer across endothelial monolayers and lipid hydroperoxides. However, an increase in lipid hydroperoxides was seen only when endothelial cell cultures were supplemented with iron. BSO treatment increased susceptibility of endothelial cells to TNF-mediated metabolic disturbances. On the other hand, NAC partially protected against TNF-induced injury to endothelial monolayers. Our results demonstrate the important role of the glutathione redox cycle in TNF-mediated disturbances of the vascular endothelium and indicate that modulation of glutathione levels may potentiate the injurious effects of this inflammatory cytokine.

Original languageEnglish
Pages (from-to)179-188
Number of pages10
Issue number2
StatePublished - Oct 1995

Bibliographical note

Funding Information:
We gratefully thank Dr. Mary A. Stuart for reviewing the manuscript. This research was supported in part by grants from the National Heart, Lung and Blood Institute, National Institutes of Health, Veterans’ Administration, Dairy Management, Inc., and the Kentucky Agricultural Experimental Station.


  • Atherosclerosis
  • Buthionine sulfoximine
  • Endothelial barrier function
  • Inflammatory cytokines
  • Intracellular calcium
  • N-acetyl-L-cysteine
  • Oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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