Zinc deficiency induces vascular pro-inflammatory parameters associated with NF-kappaB and PPAR signaling.
OBJECTIVE
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.


METHODS
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-kappaB DNA binding activity, and induced COX-2 and E-selectin gene expression, as well as monocyte adhesion in cultured endothelial cells. The NF-kappaB inhibitor CAPE significantly reduced the zinc deficiency-induced COX-2 expression, suggesting regulation through NF-kappaB signaling. PPAR can inhibit NF-kappaB signaling, and our previous data have shown that PPAR transactivation activity requires adequate zinc. Zinc deficiency down-regulated PPARalpha expression in cultured endothelial cells. Furthermore, the PPARgamma 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 IkappaBalpha 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.
Shen
Huiyun
H
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Oesterling
Elizabeth
E
Stromberg
Arnold
A
Toborek
Michal
M
MacDonald
Ruth
R
Hennig
Bernhard
B
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology; D002109:Caffeic Acids / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives; D011973:Receptors, LDL / Q000172:deficiency; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D015032:Zinc / Q000172:deficiency* / Q000502:physiology
D002109:Caffeic Acids; D016328:NF-kappa B; D047492:Peroxisome Proliferator-Activated Receptors; D011973:Receptors, LDL; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D051546:Cyclooxygenase 2; C055494:caffeic acid phenethyl ester; D015032:Zinc; D010626:Phenylethyl Alcohol