Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 296, Issue 4, Pages C811-C820Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00643.2008
Keywords
inducible nitric oxide synthase; zinc signaling; oxidative stress; glutamate cysteine ligase; Nrf2
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Funding
- Deutsche Forschungsgemeinschaft [SFB 503, A3]
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Cortese-Krott MM, Suschek CV, Wetzel W, Kroncke KD, Kolb-Bachofen V. Nitric oxide-mediated protection of endothelial cells from hydrogen peroxide is mediated by intracellular zinc and glutathione. Am J Physiol Cell Physiol 296: C811-C820, 2009. First published February 4, 2009; doi:10.1152/ajpcell.00643.2008.-Oxidative stress may cause endothelial dysfunction and vascular disease. It has been shown that NO protects endothelial cells (EC) against H2O2-induced toxicity. In addition, it is known that NO within cells induces a zinc release from proteins containing zinc-sulfur complexes. The aim of this study was to investigate whether zinc released intracellularly by NO plays a signaling role in the NO-mediated protection against H2O2 in rat aortic EC. Our results show that the NO-mediated protection toward H2O2 depends on the activities of glutathione peroxidase and glutamate cysteine ligase (GCL), the rate-limiting enzyme of glutathione (GSH) de novo biosynthesis. Moreover, NO increases the synthesis of the antioxidant GSH by inducing the expression of the catalytic subunit of GCL (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 proinflammatory conditions, both cellular NO synthesis and intracellular free zinc are required to maintain the cellular GSH levels. Using RNA interference and laser scanning microscopy, we found that the NO-induced expression of GCLC depends on the activation of the transcription factor Nrf2 but not on the activity of the zinc- sensing transcription factor MTF-1. 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.
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