TY - JOUR
T1 - Zinc Deficiency Induces Vascular Pro-Inflammatory Parameters Associated with NF-κB and PPAR Signaling
AU - Shen, Huiyun
AU - Oesterling, Elizabeth
AU - Hennig, Bernhard
AU - Hennig, Bernhard
AU - Stromberg, Arnold
AU - Toborek, Michal
AU - MacDonald, Ruth
PY - 2008/10/1
Y1 - 2008/10/1
N2 - 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-κB DNA binding activity, and induced COX-2 and E-selectin gene expression, as well as monocyte adhesion in cultured endothelial cells. The NF-κB inhibitor CAPE significantly reduced the zinc deficiency-induced COX-2 expression, suggesting regulation through NF-κB signaling. PPAR can inhibit NF-κB signaling, and our previous data have shown that PPAR transactivation activity requires adequate zinc. Zinc deficiency down-regulated PPARα expression in cultured endothelial cells. Furthermore, the PPARγ 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 IκBα 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.
AB - 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-κB DNA binding activity, and induced COX-2 and E-selectin gene expression, as well as monocyte adhesion in cultured endothelial cells. The NF-κB inhibitor CAPE significantly reduced the zinc deficiency-induced COX-2 expression, suggesting regulation through NF-κB signaling. PPAR can inhibit NF-κB signaling, and our previous data have shown that PPAR transactivation activity requires adequate zinc. Zinc deficiency down-regulated PPARα expression in cultured endothelial cells. Furthermore, the PPARγ 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 IκBα 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.
KW - Endothelial cells
KW - Inflammation
KW - LDL-R-deficient mouse
KW - NF-κB
KW - PPAR
KW - Zinc deficiency
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U2 - 10.1080/07315724.2008.10719741
DO - 10.1080/07315724.2008.10719741
M3 - Article
C2 - 18845708
AN - SCOPUS:58149393439
SN - 0731-5724
VL - 27
SP - 577
EP - 587
JO - Journal of the American College of Nutrition
JF - Journal of the American College of Nutrition
IS - 5
ER -