Zinc protects endothelial cells from hydrogen peroxide via Nrf2-dependent stimulation of glutathione biosynthesis.
Oxidative stress is one of the main causes of vascular disease. This study aims to investigate the antioxidant activity exerted by zinc in primary rat endothelial cells (EC). Using a 24-h treatment with hydrogen peroxide as a model for oxidative stress, we found that zinc supplementation protects from peroxide-induced cell death via increasing the transcription of the catalytic subunit (heavy chain) of glutamate-cysteine ligase (GCLC) and the concentrations of glutathione (GSH). Conversely, zinc depletion significantly decreased the expression of GCLC and the cellular GSH levels, resulting in an increased susceptibility of EC to oxidative stress. Using confocal microscopy and the RNA silencing technique, we found that zinc upregulates the expression of GCLC by activating the transcription factor Nrf2. Surprisingly, the intracellular zinc sensor, metal-responsive transcription factor-1, is not involved in the zinc-induced expression of GCLC. The present study shows that zinc controls the redox state of EC by regulating the de novo synthesis of GSH. This molecular mechanism may contribute to the elaboration of new nutritional and/or pharmaceutical approaches for protecting the endothelium against oxidative stress.
Cortese
Miriam M
MM
Institute of Molecular Medicine, Research Group Immunobiology, Medical Faculty of the Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany. mcortese@ukaachen.de
Suschek
Christoph V
CV
Wetzel
Wiebke
W
Kröncke
Klaus-D
KD
Kolb-Bachofen
Victoria
V
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis*; D005978:Glutathione / Q000096:biosynthesis*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D015032:Zinc / Q000502:physiology*; D019287:Zinc Sulfate / Q000494:pharmacology; D000097809:Transcription Factor MTF-1
D004268:DNA-Binding Proteins; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D006861:Hydrogen Peroxide; D051267:NF-E2-Related Factor 2; D014157:Transcription Factors; D015032:Zinc; D019287:Zinc Sulfate; D000097809:Transcription Factor MTF-1; C495637:Nfe2l2 protein, rat