Journal of the American College of Nutrition, Vol 16, Issue 5 411-417, Copyright © 1997 by American College of Nutrition

JOURNAL ARTICLE

Zinc attenuates tumor necrosis factor-mediated activation of transcription factors in endothelial cells

P. Connell, V. M. Young, M. Toborek, D. A. Cohen, S. Barve, C. J. McClain and B. Hennig
Multidisciplinary Doctoral Program in Nutritional Sciences, University of Kentucky, Lexington 40506-0054, USA.

OBJECTIVE: The objective of the study was to test the hypothesis that zinc can protect against endothelial dysfunction by interfering with oxidative stress-mediated cellular signaling and subsequent inhibition of an endothelial cell inflammatory response. Our approach was to compare alterations on molecular and biochemical levels with changes in endothelial barrier function that occur in zinc deficient conditions. METHODS: To investigate our hypothesis, endothelial cells were exposed to zinc deficient media for 2 to 10 days to deplete cellular zinc stores. Following this, half of the groups received zinc supplementation (9.2 microM) for 48 hours. The other half served as zinc deficient controls. These cells were then challenged with tumor necrosis factor-alpha (TNF) for varying time periods. Nuclear extracts were prepared from cells and analyzed for nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) binding. Media from cells were analyzed for interleukin 8 (IL-8) production, and cellular proteins were determined. RESULTS: Zinc supplementation resulted in a 74% increase in cellular zinc content. It was also shown that a 1.5 hour exposure to TNF (100 U/mL medium) significantly increased NF-kappa B and AP-1 binding, which was lowered considerably when cells were supplemented with physiological levels of zinc. Zinc supplementation also caused a marked attenuation in IL-8 expression by endothelial cells in response to TNF-mediated cell activation. DISCUSSION: Our previous data clearly show that zinc is a protective and critical nutrient for maintenance of endothelial integrity. The present data suggest that zinc may protect against cytokine-mediated activation of oxidative stress sensitive transcription factors, upregulation of inflammatory cytokines and endothelial cell dysfunction. This may have implications in understanding mechanisms of atherosclerosis.

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