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Departments of Nutrition and Food Science (B.H., P.M.), Neurosurgery (M.T.), and Medicine (C.J.M.), University of Kentucky, Lexington, Kentucky
Address reprint requests to: Bernhard Hennig, PhD, FACN, Cell Nutrition Group, Department of Nutrition and Food Science, 204 Funkhouser Building, University of Kentucky, KY 40506-0054
Objective: The objective of this study was to test the hypothesis that zinc deficiency in endothelial cells may potentiate the inflammatory response mediated by certain lipids and cytokines, possibly via mechanisms associated with increased cellular oxidative stress. Our experimental approach was to compare conditions of cellular zinc deficiency and zinc supplementation with oxidative stress-mediated molecular and biochemical changes in vascular endothelial cells.
Methods: To investigate our hypothesis, porcine pulmonary artery-derived endothelial cells were depleted of zinc by culture in media containing 1% fetal bovine serum for eight days. Subsequently, endothelial cells were exposed to media enriched with or without zinc (10 µM) for two days, followed by exposure to either tumor necrosis factor-
(TNF, 500 U/mL) or linoleic acid (90 µM), before measurement of oxidative stress (DCF fluorescence), activation of nuclear factor 
B (NF-B) or activator protein-1 (AP-1) and production of the inflammatory cytokine interleukin 6 (IL-6).
Results: Oxidative stress was increased markedly in zinc-deficient endothelial cells following treatment with fatty acid or TNF. This increase in oxidative stress was partially blocked by prior zinc supplementation. The oxidative stress-sensitive transcription factor NF-B was up-regulated by zinc deficiency and fatty acid treatment. The up-regulation mediated by fatty acids was markedly reduced by zinc supplementation. Similar results were obtained with AP-1. Furthermore, endothelial cell production of IL-6 was increased in zinc-deficient endothelial cells following treatment with fatty acids or TNF. This increase in production of inflammatory cytokines was partially blocked by zinc supplementation.
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 in part be antiatherogenic by inhibiting oxidative stress-responsive events in endothelial cell dysfunction. This may have implications in understanding mechanisms of atherosclerosis.
Key words: Zinc, antioxidant, NF-B, AP-1, cytokines, TNF, IL-6, atherosclerosis
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