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975884 
Journal Article 
Abstract 
Nitric oxide induces the synthesis of glutathione and protects endothelial cells towards hydrogen peroxide via "free" zinc 
Cortese-Krott, MM; Suschek, CV; Wetzel, W; Kroncke, KD; Kolb-Bachofen, V 
2008 
Yes 
Free Radical Biology and Medicine
ISSN: 0891-5849
EISSN: 1873-4596 
45 
Suppl. 
S112-S112 
English 
WOS:000260867900318 
is part of a larger document 3452652 SFRBM's 15th Annual Meeting: Program and Abstracts
We have recently shown that zinc increases the synthesis of the antioxidant glutathione (GSH) by increasing the expression of the catalytic subunit of glutamate cysteine ligase (GCLC), the rate-limiting enzyme of GSH de novo biosynthesis, and in this way protects endothelial cells (EC) against H2O2-induced toxicity [1]. High output nitric oxide (NO) synthesis induces zinc release from proteins containing zinc sulfur clusters and, similarly to zinc, protects EC against H2O2-induced toxicity. Thus, in the present study we investigated whether “free” zinc released by NO within the cells plays a signaling role in the NO-mediated protection against H2O2 in EC. We found that the NO-mediated protection towards H2O2 depends on the NO-mediated increase of GSH via inducing the expression of GCLC. Chelating intracellular “free” zinc abrogates the NO-mediated increase of GCLC and of cellular GSH levels. As a consequence, the NO-mediated protection against H2O2-induced toxicity is impaired. We also show that under pro-inflammatory conditions both inhibition of endogenous NO synthesis and chelation of intracellular “free” zinc decreases the cellular GSH levels and increases the H2O2-induced toxicity. By using RNA interference and confocal microscopy we found that NO-induced expression of GCLC is dependent on the activation of the transcription factor Nrf2. These findings show that intracellular “free” zinc plays a signaling role in the protective activity of NO, and could explain why maintenance of an adequate zinc status in the endothelium is important to protect from oxidative stress and the development of vascular disease.

[1] Cortese, M. M.; Suschek, C. V.; Wetzel, W.; Kröncke, K. D.; Kolb-Bachofen, V. Zinc protects endothelial cells from hydrogen peroxide via Nrf2-dependent stimulation of glutathione biosynthesis. Free Radic Biol Med 44:2002-2012; 2008. 
Society for Free Radical Biology and Medicine 15th Annual Meeting 
Indianapolis, IN 
November 19-23, 2008