Progress 07/15/01 to 07/14/06
Outputs
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 treatment with linoleic acid or TNF-alpha and zinc deficiency was induced by 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.
Impacts
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
- 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)
- 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) Activation of PPAR reduces PCB-induced endothelial activation: possible 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.
- 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.
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Progress 01/01/05 to 12/31/05
Outputs
Zinc requirements of the endothelium are increased during inflammatory conditions that exist in cardiovascular diseases, such as atherosclerosis. Because atherosclerosis is a disease marked by oxidative stress and chronic inflammation, the antioxidant and anti-inflammatory properties of zinc are of obvious importance in the prevention of cardiovascular diseases. We have shown that vascular endothelial cells experience increased oxidative stress and inflammatory parameters during zinc deficiency. The anti-inflammatory properties of zinc are not well understood. Zinc has multiple roles in maintaining the physiological conditions of the cardiovasculature. 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. Our current work focuses in part on the effect of zinc deficiency on the anti-inflammatory properties of peroxisome proliferator activated receptors (PPARs). Zinc deficiency by itself can upregulate the expression of pro-inflammatory genes in vascular tissues and down-regulate anti-inflammatory protein expression such as PPARs. Furthermore, using PPAR agonists we found that adequate dietary zinc is critical for proper PPAR signaling and thus the protective properties of PPARs. Our data also suggest 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.
Impacts
The average Kentuckian has poor dietary habits (high intake of processed foods rich in fat and low in fruits and vegetables) which contribute to poor health. Thus, 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 micronutrients, including minerals like zinc can provide effective protection against the harmful effects of high-fat diets. 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 antiatherogenic role of zinc appears to be in its ability to inhibit oxidative stress-responsive and inflammatory
factors involved in disruption of endothelial integrity and atherosclerosis. Thus, whole foods rich in health-promoting minerals and vitamins should be included in every meal.
Publications
- Flora G., Pu, H., Lee, Y.W., Ravikumar, R., Nath, A., Hennig, B., Toborek, M. Proinflammatory synergism of ethanol and HIV-1 Tat protein in brain tissue. Exp Neurol, 191: 2-12, 2005.
- Hennig, B., Reiterer, G., Toborek, M., Matveev, S.V., Daugherty, A., Smart, E., Robertson, L. Dietary fat interacts with PCBs to induce changes in lipid metabolism in LDL receptor deficient mice. Environ Health Perspect, 113: 83-87, 2005.
- Toborek, M., Lee, Y.W., Flora, G., Pu, H., Andras, I.E., Wylegala, E., Hennig, B., Nath, A. Mechanisms of blood-brain barrier disruption in HIV-1 infection. Cellular and Molecular Neurobiology 25: 181-199, 2005.
- Hayashi, K., Pu, H., Tian, J., Andras, I.E., Lee, Y.W., Hennig, B., Toborek, M. HIV-Tat protein induces P-glycoprotein expression in brain microvascular endothelial cells. J Neurochem 93:1231-1241, 2005.
- Hennig, B., Reiterer, G., Majkova, Z., Oesterling, E., Meerarani, P., Toborek, M. Modification of environmental toxicity by nutrients: implications in atherosclerosis. Cardiovasc Toxicol 5:153-60, 2005.
- Reiterer, G., MacDonald, R., Browning, J.D., Marrow, J., Matveev, S.V., Daugherty, A., Smart, E., Toborek, M., Hennig, B. Zinc deficiency induces atherogenic events in LDL-R-deficient mice. J Nutr, 135:2114-2118, 2005.
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Progress 01/01/04 to 12/31/04
Outputs
Zinc has multiple roles in maintaining the physiological conditions of the cardiovasculature. Because zinc is required for normal cellular repair processes, and because cardiovascular diseases, such as atherosclerosis, 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. Thus, zinc requirements of the endothelium are increased during inflammatory conditions that exist in cardiovascular disease. However, protective mechanisms of zinc in maintaining normal functions of endothelial cells are still unclear. Because atherosclerosis is a disease marked by oxidative stress and chronic inflammation, the antioxidant and anti-inflammatory properties of zinc are of obvious importance in the prevention of cardiovascular diseases. The anti-inflammatory properties of zinc are not well understood. Zinc is involved in multiple cell signaling
pathways, implicated in the pathogenesis of atherosclerosis. Our work focuses in part on the effect of zinc deficiency on the anti-inflammatory properties of peroxisome proliferator activated receptors (PPARs). Using PPAR agonists we discovered that adequate dietary zinc is critical for proper PPAR signaling and thus the protective properties of PPARs. 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 a critical nutritive and therapeutic role in inflammatory diseases such as atherosclerosis.
Impacts
The average Kentuckian has poor dietary habits (high intake of processed foods rich in fat and low in fruits and vegetables), which contribute to poor health. Thus, 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 micronutrients, including minerals like zinc can provide effective protection against the harmful effects of high-fat diets. 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 antiatherogenic role of zinc appears to be in its ability to inhibit oxidative stress-responsive and inflammatory
factors involved in disruption of endothelial integrity and atherosclerosis. Thus, whole foods rich in health-promoting minerals and vitamins should be included in every meal.
Publications
- Hennig, B., Toborek, M. Nutrition, environmental pollution and vascular endothelial cell function: implications in atherosclerosis. International Atherosclerosis Society (http://www.athero.org/), May 2004 (http://www.athero.org/nutrition.asp).
- Hennig, B., Toborek, M., Bachas, L.G., Suk, W.A. Emerging issues: nutritional awareness in environmental toxicology. J Nutr Biochem. 2004 Apr;15(4):194-5.
- Reiterer, G., Toborek, M., Hennig, B. Quercetin protects against linoleic acid-induced porcine endothelial cell dysfunction. J Nutr. 2004 Apr;134(4):771-5.
- Saraswathi, V., Wu, G., Toborek, M., Hennig, B. Linoleic acid-induced endothelial activation: role of calcium and peroxynitrite signaling. J Lipid Res. 2004 May;45(5):794-804.
- Lee, Y.W., Eum, S.Y., Chen, K.C., Hennig, B., Toborek M. Gene expression profile in interleukin-4-stimulated human vascular endothelial cells. Mol Med. 2004 Jan-Jun;10(1-6):19-27.
- Chalimoniuk, M., King-Pospisil, K., Pedersen, W.A., Malecki, A., Wylegala, E., Mattson, M.P., Hennig, B, Toborek M. Arachidonic acid increases choline acetyltransferase activity in spinal cord neurons through a protein kinase C-mediated mechanism. J Neurochem. 2004 Aug;90(3):629-36.
- Reiterer, G., Toborek, M., Hennig, B. Peroxisome proliferator activated receptors alpha and gamma require zinc for their anti-inflammatory properties in porcine vascular endothelial cells. J Nutr. 2004 Jul;134(7):1711-5.
- Eum, S.Y., Lee, Y.W., Hennig, B., Toborek, M. VEGF regulates PCB 104-mediated stimulation of permeability and transmigration of breast cancer cells in human microvascular endothelial cells. Exp Cell Res. 2004 Jun 10;296(2):231-44.
- Ravikumar, R., Flora, G., Geddes, J.W., Hennig, B., Toborek M. Nicotine attenuates oxidative stress, activation of redox-regulated transcription factors and induction of proinflammatory genes in compressive spinal cord trauma. Brain Res Mol Brain Res. 2004 May 19;124(2):188-98.
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Progress 01/01/03 to 12/31/03
Outputs
Zinc requirements of the endothelium are increased during inflammatory conditions that exist in cardiovascular disease. However, protective mechanisms of zinc in maintaining normal functions of endothelial cells are still unclear. Because of its constant exposure to blood components, including prooxidants, inflammatory cytokines, diet-derived fats and their derivatives, the endothelium is very susceptible to oxidative stress and dysfunction. Thus, it is very likely that certain diet-derived fats, especially unsaturated fats, can greatly alter the cellular lipid and oxidant/antioxidant environment and thus further compromise normal endothelial integrity during zinc deficiency. We have evidence that zinc deficiency augments proinflammatory effects of specific fatty acids in endothelial cells that can lead to increased atherogenesis. Dietary zinc has potent antioxidant and antiinflammatory properties and is a critical component of peroxisome proliferator-activated
receptor (PPAR) gene expression and regulation. Our data indicate that zinc plays a critical role in PPAR signaling during endothelial cell activation and that PPAR signaling is impaired during zinc deficiency. This may explain in part the protective mechanisms of zinc against endothelial cell dysfunction and atherosclerosis. Zinc may have a critical nutritive and therapeutic role in inflammatory diseases such as atherosclerosis.
Impacts
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 refined foods, and lack of protective nutrients such as antioxidants. Sufficient consumption of micronutrients, including minerals like zinc can provide effective protection against the harmful effects of refined high-calorie diets. Dietary zinc has potent antioxidant and anti-inflammatory properties. Our research suggests that diet-derived zinc can provide protection against cardiovascular diseases such as atherosclerosis by preventing metabolic and physiologic dysfunction of the vascular endothelium. Foods in the meat group (beef) contribute to about 50% of the zinc available in the daily food supply. Beef cattle operations are rapidly expanding in Kentucky, contributing significantly to the total economic impact. Our research contributes to
a more positive nutrition message about beef, thus alleviating consumer confusion and uncertainty about beef-related diet and health advice.
Publications
- Lee, Y.W., Hennig B., Toborek M.. Redox-regulated mechanisms of interleukin-4-induced MCP-1 expression in human vascular endothelial cells. Am. J. Physiol., 284: H185-192, 2003.
- Flora G., Lee Y.W., Nah A., Hennig B., Maragos W., Toborek M.. Methamphetamine potentiates HIV-1 Tat protein-mediated activation of redox-sensitive pathways in discrete regions of the brain. Exp. Neurol., 179, 60-70, 2003.
- Toborek M., Lee Y.W., Pu H., Malecki A., Flora G., Garrido R., Hennig B., Bauer H.C., Nath A.. HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. J. Neurochem., 84: 169-179, 2003.
- Hennig B, Toborek M, Robertson LW. Nutrition and proinflammatory mechanisms of PCB toxicity in the vascular endothelium. Fresen. Environ. Bull., 12: 240-244, 2003.
- Meerarani P, Smart EJ, Toborek M, Boissonneault GA, Hennig B. Cholesterol attenuates linoleic acid-induced endothelial cell activation. Metabolism, 52(4):493-500, 2003.
- Lee, Y.W., H.J. Park, K.W. Son, B. Hennig, L.W. Robertson and M. Toborek. 2,2'4,4',6'-Pentachlorobiphenyl (PCB 104) induces apoptosis of human microvascular endothelial cells through the caspase-dependent activation of CREB. Toxicol. Appl. Pharmacol., 189: 1-10, 2003.
- Meerarani P, Reiterer G, Toborek M, Hennig B. Zinc modulates PPAR signaling and activation of endothelial cells. J. Nutr., 133: 3049-3055, 2003.
- Ramadass P, Meerarani P, Toborek M, Robertson LW, Hennig B. Dietary flavonoids modulate PCB-induced oxidative stress, CYP1A1 induction and AhR DNA binding activity in vascular endothelial cells. Toxicol. Sci., 76: 212-219, 2003.
- Garrido R, King-Pospisil K, Son KW, Hennig B, Toborek M. Nicotine upregulates nerve growth factor expression and prevents apoptosis of cultured spinal cord neurons. Neurosci. Res., 47: 349-355, 2003.
- Pu H, Tian J, Flora G, Lee YW, Nath A, Hennig B, Toborek M: HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain. Mol. Cell. Neurosci., 24: 224-237, 2003.
- Garrido R, Springer JE, Hennig B, Toborek M. Nicotine attenuates arachidonic acid-induced apoptosis of spinal cord neurons by preventing depletion of neurotrophic factors. J. Neurotrauma, 20: 1201-1213, 2003.
- Saraswathi V, Hammock BD, Newman JW, Meerarani P, Toborek M, Hennig B. Involvement of CYP 2C9 in mediating the proinflammatory effects of linoleic acid in vascular endothelial cells. J. Am. Coll. Nutr., 502-510, 2003.
- Andras IE, Pu H, Deli MA, Nath A, Hennig B, Toborek M. HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells. J. Neurosci. Res., 74: 255-265, 2003.
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Progress 01/01/02 to 12/31/02
Outputs
Little is known about the requirements and function of zinc in maintaining endothelial cell integrity, especially during stressful conditions, such as the inflammatory response in cardiovascular disease. Because zinc is required for normal cellular repair processes, and because atherosclerosis is believed to begin with vessel wall activation and dysfunction, a depressed zinc status may be involved in either initiation of cell injury or inadequate vascular tissue repair. Thus, zinc requirements of the endothelium are increased during inflammatory conditions that exist in cardiovascular disease. However, protective mechanisms of zinc in maintaining normal functions of endothelial cells are still unclear. Because of its constant exposure to blood components, including prooxidants, inflammatory cytokines, diet-derived fats and their derivatives, the endothelium is very susceptible to oxidative stress and dysfunction. Thus, it is very likely that certain diet-derived fats,
especially unsaturated fats, can greatly alter the cellular lipid and oxidant/antioxidant environment and thus further compromise normal endothelial integrity during zinc deficiency. We have evidence that zinc deficiency augments proinflammatory effects of specific fatty acids in endothelial cells that can lead to increased atherogenesis. Our data suggest that zinc can downregulate the pathways of signal transduction leading to an inflammatory response and to disruption of endothelial cell integrity. Zinc may have a critical nutritive and therapeutic role in inflammatory diseases such as atherosclerosis.
Impacts
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 overconsumption of calories and especially fat, and lack of protective nutrients such as antioxidants. Sufficient consumption of micronutrients, including minerals like zinc can provide effective protection against the harmful effects of high-fat diets. 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 antiatherogenic role of zinc appears to be in its ability to inhibit oxidative stress-responsive and inflammatory factors involved in disruption of endothelial integrity and atherosclerosis. Thus, whole foods rich in health-promoting minerals and vitamins should be included in every meal.
Publications
- Hennig, B., P. Meerarani, R. Slim, M. Toborek, A. Daugherty, A. Silverstone, and L.W. Robertson. Proinflammatory properties of co-planar PCBs: in vitro and in vivo evidence. Toxicol. Appl. Pharmacol., 181: 174-183, 2002.
- Flora, G., Y.W. Lee, A. Nath, W. Maragos, B. Hennig and M. Toborek. Methamphetamine-induced TNF-alpha gene expression and activation of AP-1 in discrete regions of mouse brain: potential role of reactive oxygen intermediates and lipid peroxidation. J. Molec. Neurosci. 2: 71-85, 2002.
- Lee, Y.W., K.W. Son, G. Flora, B. Hennig, A. Nath and M. Toborek. Methamphetamine activates DNA-binding of specific redox-responsive transcription factors in mouse brain. J. Neurosci. Res., 70: 82-89, 2002.
- Toborek, M., Y.W. Lee, R. Garrido, S. Kaiser, and B. Hennig. Dietary unsaturated fatty acids selectively induce an inflammatory environment in human endothelial cells. Am. J. Clin. Nutr., 75: 119-125. 2002.
- Park, H.J., Y.W. Lee, B. Hennig, and M. Toborek. Linoleic acid-induced VCAM-1 expression in human microvascular endothelial cells is mediated by the NF-kappaB-dependent pathway. Nutr. Cancer, 41: 126-134, 2002.
- Hennig, B., Hammock B.D., R. Slim, M. Toborek, V. Saraswathi, and L.W. Robertson. PCB-induced oxidative stress in endothelial cells: modulation by nutrients. Int. J. Hyg. Environ. Health, 205: 95-102, 2002.
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Progress 01/01/01 to 12/31/01
Outputs
We have shown that zinc is vital to endothelial integrity and that zinc deficiency causes a severe impairment of endothelial barrier function. Zinc is documented both to act as an antioxidant and to have membrane-stabilizing properties. We have previously shown that a disruption of endothelial cell monolayer integrity by TNF can be prevented by preenriching cells with zinc. We have evidence that during zinc deficiency, cellular oxidative stress is markedly induced by exposure to linoleic acid and/or TNF and that this oxidative stress can be partially blocked by zinc supplementation. Zinc requirements of the vascular endothelium may be increased during inflammatory conditions such as atherosclerosis, where apoptotic cell death is also prevalent. Zinc is a critical component in the protection against cell destabilizing agents such as polyunsaturated lipids and inflammatory cytokines. There is evidence that zinc is a potent inhibitor of apoptosis and that zinc deficiency
can induce apoptosis. The subcellular mechanisms by which zinc affects apoptosis are not well understood and may occur at multiple levels. It has been reported that part of the protective mechanisms of zinc appears to be via inhibition of caspases, such as caspase 3. Our data suggests that certain dietary fats rich in linoleic acid and inflammatory cytokines (such as TNF) can independently, but more markedly in concert, induce caspase 3 activity in endothelial cells. Furthermore, our present data also demonstrate that zinc can protect against linoleic acid and/or TNF-induced endothelial cell apoptosis. The long-term goals of this research are to determine zinc nutrition and requirements of endothelial cells, with implications of understanding the protective role of zinc in diseases or disorders such as atherosclerosis. This research is relevant to U.S. Agriculture. Atherosclerosis is a significant cause of poor health in America, and the proposed studies may help to explain the
influence of zinc malnutrition on this disease, especially in people who consume high-fat fats.
Impacts
Kentuckians are experiencing a high incidence of nutrition-related health problems, which may be due to overconsumption of fat and lack of protective nutrients such as antioxidants. Sufficient consumption of micronutrients, including minerals like zinc can provide effective protection against the harmful effects of high-fat diets. Our research suggests that diet-derived zinc can provide antiatherogenic properties by preventing metabolic physiologic derangement of the vascular endothelium. The antiatherogenic role of zinc appears to be in its ability to inhibit oxidative stress-responsive factors involved in disruption of endothelial integrity and atherosclerosis.
Publications
- Lee, Y.W., H. Kuhn, B. Hennig, A.S. Neish and M. Toborek. IL-4-induced oxidative stress upregulates VCAM-1 gene expression in human endothelial cells. J. Mol. Cell. Cardiol., 33: 83-94, 2001.
- Slim, R., B.D. Hammock, M. Toborek, L.W. Robertson, J.W. Newman, C.H.P. Morisseau, B.A. Watkins, V. Saraswathi and B. Hennig. The role of methyl-linoleic acid epoxide and diol metabolites in the amplified toxicity of linoleic acid and polychlorinated biphenyls to vascular endothelial cells. Toxicol. Appl. Pharmacol., 171: 184-193, 2001.
- Hennig, B., and M. Toborek. Nutrition and Endothelial Cell Function: Implications in Atherosclerosis. Nutr. Res., 21: 279-293, 2001
- Garrido, R., M.P. Mattson, B. Hennig, and M. Toborek. Nicotine protects against arachidonic acid-induced caspase activation, cytochrome c release, and apoptosis of cultured spinal cord neurons. J. Neurochem., 76: 1395-1403, 2001.
- Hennig, B., M. Toborek, and C.J. McClain. High-energy nutrients, fatty acids and endothelial cell function: implications in atherosclerosis. J. Am. Coll. Nutr., 20: 97-105, 2001.
- Lee, Y.W., H. Kuhn, S. Kaiser, B. Hennig, A. Daugherty, and M. Toborek. Interleukin-4 induces transcription of the 15-lipoxygenase-I gene in human endothelial cells. J. Lipid Res., 42: 783-791, 2001.
- Lee, Y.W., H.J. Park, B. Hennig, and M. Toborek. Linoleic acid induces MCP-1 gene expression in human microvascular endothelial cells through an oxidative mechanism. J. Nutr. Biochem., 12: 648-654, 2001.
- Lee, Y.W., B. Hennig, M. Fiala, and M. Toborek. Cocaine activates redox-regulated transcription factors and induces TNF expression in human brain endothelial cells. Brain Res., 920: 125-133, 2001.
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