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Zinc Deficiency Induces Vascular Pro-Inflammatory Parameters Associated with NF-B and PPAR Signaling

Graduate Center for Toxicology (H.S., E.O., B.H.)
Molecular and Cell Nutrition Laboratory (B.H.)
College of Agriculture, Departments of Statistics (A.S.)
Neurosurgery (M.T.)
University of Kentucky, Lexington, Kentucky, Department of Food Science and Human Nutrition (R.M.), Iowa State University, Ames, Iowa

Address correspondence to: Bernhard Hennig, PhD, RD, FACN, C.T. Wethington Building, Room 599, University of Kentucky, Lexington, KY 40536. E-mail: bhennig{at}email.uky.edu

Objectives: Marginal intake of dietary zinc can be associated with increased risk of cardiovascular diseases. In the current study we hypothesized that vascular dysfunction and associated inflammatory events are activated during a zinc deficient state.

Design: We tested this hypothesis using both vascular endothelial cells and mice lacking the functional LDL-receptor gene.

Results: Zinc deficiency increased oxidative stress and NF-B DNA binding activity, and induced COX-2 and E-selectin gene expression, as well as monocyte adhesion in cultured endothelial cells. The NF-B inhibitor CAPE significantly reduced the zinc deficiency-induced COX-2 expression, suggesting regulation through NF-B signaling. PPAR can inhibit NF-B signaling, and our previous data have shown that PPAR transactivation activity requires adequate zinc. Zinc deficiency down-regulated PPAR expression in cultured endothelial cells. Furthermore, the PPAR agonist rosiglitazone was unable to inhibit the adhesion of monocytes to endothelial cells during zinc deficiency, an event which could be reversed by zinc supplementation. Our in vivo data support the importance of PPAR dysregulation during zinc deficiency. For example, rosiglitazone induced inflammatory genes (e.g., MCP-1) only during zinc deficiency, and adequate zinc was required for rosiglitazone to down-regulate pro-inflammatory markers such as iNOS. In addition, rosiglitazone increased IB protein expression only in zinc adequate mice. Finally, plasma data from LDL-R-deficient mice suggest an overall pro-inflammatory environment during zinc deficiency and support the concept that zinc is required for proper anti-inflammatory or protective functions of PPAR.

Conclusions: These studies suggest that zinc nutrition can markedly modulate mechanisms of the pathology of inflammatory diseases such as atherosclerosis.

Key words: zinc deficiency, inflammation, endothelial cells, LDL-R-deficient mouse, NF-B, PPAR

Abbreviations: AP-1 = activator protein-1 • ApoE^–/– = apolipoprotein E deficient • CAPE = caffeic acid phenethyl ester • COX-2 = cyclooxygenase-2 • EMSA = electrophoretic mobility shift assay • E-selectin = endothelial cell selectin • FBS = fetal bovine serum • HBSS = HEPES buffered salt solution • H₂DCF-DA = 2',7'-dichlorodihydrofluorescein diacetate • IB = NF-B inhibitor • IL = interleukin • iNOS = inducible nitric oxide synthase • LDL = low density lipoprotein • LDL-R^–/– = LDL-receptor deficient • MCP-1 = monocyte chemotactic protein-1 • MGBNFQ = minor groove binder/non-fluorescent quencher • MT = metallothionein • NF-B = nuclear factor-B • NO = nitric oxide • PMSF = phenylmethanesulfonyl fluoride • PPAR = peroxisome proliferator activated receptor • PPRE = peroxisome proliferator response element • ROS = reactive oxygen species • RSG = rosiglitazone • RXR = retinoid X receptor • TBST = tris-buffered saline containing 0.1% tween 20 • TPEN = N,N,N',N'-Tetrakis (2-pyridylmethyl) ethylene diamine