Cellular glutathione status modulates polychlorinated biphenyl-induced stress response and apoptosis in vascular endothelial cells

R. Slim, Michal J Toborek, L. W. Robertson, H. J. Lehmler, B. Hennig

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs), may severely compromise normal function of vascular endothelial cells (EC). We have previously shown that PCB 77 (3,3',4,4'-tetrachlorobiphenyl), an arylhydrocarbon receptor (AhR) agonist, can induce oxidative stress in cultured EC. We now show that PCB 77 can activate EC and induce a cellular stress response that is reflected by the activation of c-Jun N-terminal/stress-activated protein kinases (JNK/SAPK). Our data also suggest that this PCB 77-mediated stress response can be modulated by the intracellular glutathione content. EC treated with buthionine-sulphoximine (BSO), an inhibitor of glutathione synthesis, further enhanced PCB-induced JNK/SAPK activity. This stress response was sustained only in the presence of BSO plus PCB 77. Media supplementation with the glutathione precursor N-acetyl-cysteine (NAC) reduced PCB 77- induced JNK/SAPK. Intracellular glutathione also may be implicated in PCB-induced EC apoptosis. Individual treatment with PCB, BSO, or linoleic acid induced activation of caspase 3. Compared to PCB 77 alone, annexin V activity was further amplified during combined treatment with BSO and PCB 77. DNA fragmentation was mostly observed when cells were treated with both BSO and PCB 77. The caspase 3-specific inhibitor DEVD-CHO protected cells against PCB 77/BSO-mediated apoptosis and inhibited the caspase activity without affecting JNK/SAPK activation or cellular glutathione levels. These results suggest that AhR ligands, such as PCB 77, cause vascular EC dysfunction by modulating intracellular glutathione, which subsequently leads to activation of stress-specific kinases. Furthermore, inhibition of glutathione synthesis by BSO can further potentiate the PCB 77-induced stress response and ultimately lead to apoptotic cell death. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)36-42
Number of pages7
JournalToxicology and Applied Pharmacology
Volume166
Issue number1
DOIs
StatePublished - Jul 1 2000
Externally publishedYes

Fingerprint

Polychlorinated Biphenyls
Endothelial cells
Glutathione
Endothelial Cells
Apoptosis
Buthionine Sulfoximine
Chemical activation
3,4,3',4'-tetrachlorobiphenyl
Caspase 3
Acetylcysteine
Oxidative stress
CHO Cells
Annexin A5
Environmental Exposure
DNA Fragmentation
Cell death
Linoleic Acid
Caspases
Heat-Shock Proteins
Protein Kinases

Keywords

  • Apoptosis
  • Endothelial cells
  • Glutathione
  • PCB
  • Stress kinases

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Cellular glutathione status modulates polychlorinated biphenyl-induced stress response and apoptosis in vascular endothelial cells. / Slim, R.; Toborek, Michal J; Robertson, L. W.; Lehmler, H. J.; Hennig, B.

In: Toxicology and Applied Pharmacology, Vol. 166, No. 1, 01.07.2000, p. 36-42.

Research output: Contribution to journalArticle

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