Research Accomplishment Reports 2007

Nutritional Modulation of the Vascular Endothelium

B. Hennig, M. Toborek
Department of Animal and Food Sciences

 

Project Description

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. We have shown that vascular endothelial cells experience increased oxidative stress and inflammatory parameters during zinc deficiency.

Our work focuses in part on the effect of zinc deficiency on the anti-inflammatory properties of peroxisome proliferator pctivated receptors (PPARS). Zinc deficiency by itself can up regulate the expression of pro-inflammatory genes in vascular tissues and down-regulate anti-inflammatory protein expression such As PPAR. Furthermore, using PPAR agonists we found that adequate dietary zinc is critical for proper PPAR signaling and thus the protective properties of PPARS.

Results from a recent study with an atherogenic mouse model (mice which lack the LDL-R Gene) suggest that lipid metabolism is compromised during zinc deficiency and that adequate dietary zinc is critical or minimizing side effects of the anti-diabetes medicine rosiglitazone. Plasma data from LDL-R-deficient mice also 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.

Finally, recent studies in our laboratory provide evidence that zinc can protect against endothelial cell activation induced by environmental pollutants such as polychlorinated biphenyls (PCBS). Thus, zinc may have a critical nutritive and therapeutic role 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.