Antioxidant-like properties of zinc in activated endothelial cells

Objective: The objective of this study was to test the hypothesis that zinc deficiency in endothelial cells may potentiate the inflammatory response m ediated 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 wi th oxidative stress-mediated molecular and biochemical changes in vascular endothelial cells. Methods: To investigate our hypothesis, porcine pulmonary artery-derived en dothelial cells were depleted of zinc by culture in media containing 1% fet al bovine serum for eight days. Subsequently, endothelial cells were expose d to media enriched with or without zinc (10 mu M) for two days, followed b y exposure to tither tumor necrosis factor-alpha (TNF, 500 U/mL) or linolei c acid (90 mu M) before measurement of oxidative stress (DCF fluorescence), activation of nuclear factor kappa B (NF-kappa 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 endothel ial cells following treatment with fatty acid or TNF. This increase in oxid ative stress was partially blocked by prior zinc supplementation. The oxida tive stress-sensitive transcription factor NF-kappa B was up-regulated by z inc deficiency and fatty acid treatment. The up-regulation mediated by fatt y acids was markedly reduced by zinc supplementation. Similar results were obtained with AP-1. Furthermore. endothelial cell production of IL-6 was in creased in zinc-deficient endothelial cells following treatment with fatty acids or TNF. This increase in production of inflammatory cytokines was par tially blocked by zinc supplementation. Discussion: Our previous data clearly show that zinc is a protective and cr itical nutrient for maintenance of endothelial integrity. The present data suggest that zinc may in part be antiatherogenic by inhibiting oxidative st ress-responsive events in endothelial cell dysfunction. This may have impli cations in understanding mechanisms of atherosclerosis.