Research Accomplishment Reports 2007

Antiatherogenic Properties of Zinc

B. Hennig
Department of Animal and Food Sciences

 

Project Description

The objectives initially proposed were all completed successfully. We tested the overall hypothesis that zinc deficiency can augment pro-inflammatory effects of specific fatty acids in endothelial cells that lead to increased atherosclerosis. Indeed, our data demonstrated that zinc can inhibit the pathways of signal transduction leading to an inflammatory response and to disruption of endothelial integrity. Because zinc is required for normal cellular repair processes, and because cardiovascular diseases, such as atherosclerosis, are believed to begin with vessel wall activation and dysfunction, a depressed zinc status may be involved in either initiation of vascular endothelial cell injury or inadequate vascular tissue repair.

Protective mechanisms of zinc in maintaining normal functions of endothelial cells are still unclear. Zinc requirements of the endothelium are increased during inflammatory conditions that exist in cardiovascular diseases, such as atherosclerosis. To assess the protective mechanisms of zinc during an endothelial cell inflammatory response, endothelial cells were activated by  and zinc deficiency was induced by,treatment with linoleic acid or TNF-alpha treatment with the membrane permeable zinc chelator TPEN. We demonstrated that zinc deficiency induced oxidative stress, increased the DNA binding activity of oxidative stress-sensitive transcription factors such as NF-kappab and AP-1, and increased endothelial cell production of IL-6. Peroxisome proliferator activated receptors (PPARS) may have antiatherogenic properties. We found that zinc deficiency decreased PPAR activation and protein expression. In contrast, zinc supplementation markedly increased PPAR activation and expression, which was correlated with downregulation of DNA binding activity of NF-kappab and AP-1. Our data demonstrate that zinc exhibits potent antioxidant and anti-inflammatory properties.

Furthermore, zinc appears to protect against endothelial cell activation and inflammation by functioning as a critical component of the PPAR transcription factor complex. A recently completed in vivo study suggests that, in a mouse model that mimics human atherosclerosis, PPAR signaling is compromised during zinc deficiency and that adequate dietary zinc is critical for proper function of anti-diabetic medicines like rosiglitazone. In summary, our data suggest that zinc can downregulate the pathways of signal transduction leading to an inflammatory response and to disruption of endothelial cell integrity. Thus, zinc may have critical nutritive and therapeutic roles in inflammatory diseases such as atherosclerosis.

Impact

Kentuckians are experiencing a high incidence of nutrition-related health problems, such as obesity, cardiovascular disease, diabetes and hypertension. These and related health problems may be due in part to over-consumption of calories and especially fat, and lack of protective nutrients such as antioxidants and related bioactive compounds. Sufficient consumption of antioxidant nutrients and/or bioactive compounds found in fruits and vegetables can provide effective protection against chronic inflammatory diseases associated with severe age-related health problems. For example, our research suggests that diet-derived zinc can provide protection against cardiovascular diseases such as atherosclerosis by preventing metabolic and physiologic derangement of the vascular endothelium. The anti-atherogenic role of such protective nutrients appears to be in its ability to inhibit oxidative stress-responsive and inflammatory factors involved in disruption of vascular endothelial cells during early pathology of atherosclerosis. Thus, through education and subsequent changes in life style towards healthier dietary habits, people may be more protected against chronic diseases such as cardiovascular disease.

Publications

Hennig B, Oesterling E, Toborek M. (2007) Environmental toxicity, nutrition, and gene interactions in the development of atherosclerosis. Nutr Metab Cardiovasc Dis, 17: 162-169.

Hennig B, Ormsbee L, Bachas L, Silverstone A, Milner J, Carpenter D, Thompson C, Suk WA. (2007) Introductory comments: nutrition, environmental toxins and implications in prevention and intervention of human diseases. J Nutr Biochem, 18: 161-162.

Hennig B, Ettinger AS, Jandacek RJ, Koo S, McClain C, Seifried H, Silverstone A, Watkins B, Suk WA. (2007) Using nutrition for intervention and prevention against environmental chemical toxicity and associated diseases. Environ Health Perspect, 115: 493-495.

Umannova L, Zatloukalova J, Machala M, Krcmar P, Majkova Z, Hennig B, Kozubik A, Vondracek J. (2007) Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome P450 enzymes in rat liver "stem-like" cells. Toxicol Sci., 99:79-89.

Andras IE, Deli M, Veszelka S, Hayashi K, Hennig B, Toborek M. (2007) The NMDA and AMPA/KA receptors are involved in glutamate-induced alterations of occludin expression and phosphorylation in brain endothelial cells. J Cereb Blood Flow Metab, 27:1431-1443.

Shen H, MacDonald R, Bruemmer D, Stromberg A, Daugherty A, Li X, Toboreck M, and Hennig B. (2007) Zinc deficiency alters lipid metabolism in LDL-receptor-deficient mice treated with rosiglitazone J Nutr, 137: 2339-2345.

Arzuaga A, Reiterer G, Majkova Z, Kilgore MW, Toborek M, and Hennig B. (2007)  reduces PCB-induced endothelial activation: possibleaActivation of PPAR interactions in inflammation and atherosclerosis. Cardiovasc Toxicol, 7: 264-272.

Pu H, Hayashi K, Andras IE, Eum SY, Hennig B, Toborek M. (2007) Limited role of COX-2 in HIV Tat-induced alterations of tight junction protein expression and discruption of the blood-brain barrier. Brain Res, 1184: 333-344.

Lim EJ, Smart E, Toborek M, Hennig B. PCB 77 activates eNOS via PI3K and Akt phosphorylation in endothelial cells by a caveolin-1 dependent mechanism (SOT Meeting, 2007).

Arzuaga X, Kluemper CT, Toborek M, Hennig B. The dietary flavonoid quercetin blocks PCB77 induced pro-inflammatory responses in vascular endothelial cells (SOT Meeting, 2007).

Oesterling E, Arzuaga X, Lim EJ, Bachas L, Toborek M, Hennig B. Manufactured nano-sized alumina particles induce endothelial cell dysfunction: implications in vascular disease (SOT Meeting, 2007).

Zhong Y, Smart EJ, Couraud PO, Hennig B, Toborek M. Caveollin-1 is involved in HIV-1 Tat-induced activation of the Ras signaling and lateration sin tight junction protein expression in human brain microvascular endothelial cells. FASEB J, 21(5): A873, 2007.

Yuang W, Rha GB, Eum SY, Andras IE, Couraud PO, Hennig B, Toborek M. PPARs protect against Tat-induced dysfunction of brain endothelial cells. FASEB J, 21(5): A873, 2007.

Andras IE, Rha GB, Eum SY, Couraud PO, Hennig B, Toborek M. HIV-1 Tat protein amplifies amyloid beta-induced inflammatory gene expression in brain endothelial cells. FASEB J, 21(5): A873, 2007.

Chen l, Yokel RA, Hennig B, Toborek M. Manufactured aluminum oxide nanoparticles decrease expression of tight junction proteins in brain vasculature. FASEB J, 21(5): A873, 2007.

Eum SY, Andras IE, Couraud PO, Hennig B, Toborek M. Polychlorinated biphenyls induce proteolysis of zonula occluden proteins in human brain microvascular endothelial cells. FASEB J, 21(5): A873, 2007.
Lee MY, Hennig B, Toborek M. Nicotine attenuates iNOS and nNOS expression in a contusion model of spinal cord injury. FASEB J, 21(5): A786, 2007.

Wang L, Lim EJ, Zheng Y, Toborek M, Hennig B. Omega-3 and omega-6 fatty acids can differentially modulate signaling involved in prostaglandin synthesis. FASEB J, 21(5): A737, 2007.

Shen H, MacDonald R, Stromberg A, Daugherty A, Li XA, Toborek M, Hennig B. Anti-atherosclerotic properties of PPARgama are dysfunctional during zinc deficiency in LDL-R-/- mice treated with rosiglitazone. FASEB J, 21(5): A719-720, 2007.

Hennig B, Lim EJ, Smart E, Toborek M. Role of caveolae in PCB-induced vascular endothelial cell activation. (Dioxin 2007)

Oesterling E, Toborek M, Hennig B. Benzo[a]pyrene-induced vascular endothelial adhesion molecule expression can be disrupted by flavonoid treatment: implications in cardiovascular disease. 2007 Toxicology and Risk Assessment Conference.

Oesterling E, Toborek M, Hennig B. Benzo[a]pyrene-induced vascular endothelial adhesion molecule expression can be disrupted by selective flavonoid treatment. 10th Gill Heart Institute Cardiovascular Research Day, 2007.