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Diet and Vascular Endothelial Cell Function
Department of Animal and Food Sciences
Atherosclerosis, a chronic inflammatory disease, is still the number one cause of death in Kentucky and the United States, and especially in Kentucky. In addition to inflammatory mediators, dietary factors (e.g., fats or bioactive compounds) can either increase or decrease the risk and incidence of cardiovascular diseases by modulating vascular endothelial cell function. Little is known about the mechanisms and regulation of cellular uptake, trafficking and the protection bioactive compounds provide against endothelial cell activation and inflammatory pathways critical in the pathology of atherosclerosis.
Membrane lipid domains such as caveolae are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking. Thus, we hypothesize that caveolae are critical in the cellular actions of lipids and lipophilic bioactive compounds such as flavonoids. We also hypothesize that cellular signaling pathways can be modulated by bioactive food components and that their anti-inflammatory and anti-atherogenic effects are linked to caveolae signaling and the lipid milieu within the endothelium. These hypotheses will be tested by studying the interactions of dietary lipids with bioactive food components on vascular inflammatory parameters.
We propose to explore novel mechanisms of nutrient-mediated vascular functions and dysfunctions, and the outcome of our proposed study will lead to a better understanding of nutritional recommendations related to inflammatory diseases such as atherosclerosis. Porcine and human derived endothelial cells will be used in cell culture studies (specific aims 1 and 2), and endothelial cells derived from mice which lack the caveolin-1 gene will be used to confirm the importance of functional caveolae in vascular endothelial cell inflammation.
2011 Project Description
Nutrition and lifestyle are well-defined modulators of chronic diseases. Poor dietary habits, such as high intake of processed foods rich in fat and low intake of fruits and vegetables are clearly contributing to today's compromised quality of life not just in Kentucky but the whole United States.
We continue to test our hypothesis that nutrition or dietary choices can modulate chemical insults associated with exposure to environmental pollutants. This is especially important because nutrition can both exacerbate and attenuate many disease indicators, such as oxidative stress and inflammation, which are linked to health risks associated with exposures to toxicants.
We have evidence that atherosclerotic risk factors associated with exposure to environmental pollutants (e.g., polychlorinated biphenyls or PCBs), or modulation of toxicity by dietary nutrients, are regulated in part through caveolae signaling within the vascular endothelium. Caveolae are membrane microdomains involved in regulation of many signaling pathways, and in particular in vascular endothelial cells.
Nutrition or bioactive food components can modulate the toxicity of environmental pollutants, especially to the vasculature and cells associated with blood vessels. For example, we have demonstrated that endothelial caveolae play a role in uptake of persistent organic pollutants, an event associated with subsequent production of inflammatory mediators. Functional properties of caveolae can be modulated by dietary lipids (e.g. fatty acids) and bioactive food components (e.g., plant-derived polyphenols such as flavonoids), which changes activation of caveolae-associated signaling proteins.
Overall, our studies suggest that proper, i.e., "healthy", nutrition can positively influence the human health risks associated with exposure to mixtures of environmental chemicals. Using cell culture and animal models, we continue to explore the nutritional paradigm that incorporates a consideration of the relationships between nutrition and lifestyle, exposure to environmental toxicants, and disease. Our work might have significant implications in human well being.
In other words, nutritional interventions may provide the most sensible means to develop primary prevention strategies of diseases associated with many environmental toxic insults. Even though the concept that nutrition may modify or ameliorate the toxicity of environmental chemicals is provocative and warrants further study, the implications for human health could be significant. More research is needed to understand observed interactions of cellular toxicity mediated by environmental pollutants with nutritional interventions.
Poor dietary habits and exposure to environmental toxicants may be additive risk factors for increased disease outcome. Kentuckians are exposed to a significant amount of environmental pollutants. Kentuckians also are experiencing a high incidence of nutrition-related health problems, such as obesity, cardiovascular disease, diabetes and hypertension.
We hypothesize that diets can modulate disease risk factors associated with exposure to environmental pollutants. Our research supports the paradigm that consumption of diets high in certain fats can increase disease outcome associated with exposure to environmental pollutants. In contrast, diets high in antioxidants and anti-inflammatory nutrients and/or bioactive compounds may provide protection against many chronic diseases. For example, our research suggests that many nutrients found in fruits and vegetables 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 their 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.
Majkova Z, Layne J, Sunkara M, Morris AJ, Toborek M, Hennig B. Omega-3 fatty acid oxidation products prevent vascular endothelial cell activation by coplanar polychlorinated biphenyls. Toxicol Appl Pharmacol 251(1): 41-49, 2011.
Layne J, Majkova Z, Toborek M, Hennig B. Emerging Issues: Caveolae: a regulatory platform for nutritional modulation of inflammatory diseases. J Nutr Biochem, 22: 807-811, 2011.
Huang W, Andras IE, Rha GB, Hennig B, Toborek M. PPAR-alpha and PPAR-gamma protect against HIV-1-induced MMP-9 overexpression via caveolae-associated ERK and Akt signaling. FASEB J, 25: 3979-3988, 2011.
Lehner C, Gehwolf R, Tempfer H, Krizbai I, Hennig B, Bauer HC, Bauer H. Oxidative stress and blood-brain barrier dysfunction under particular consideration of matrix metalloproteinases. Antioxid Redox Signal, 15: 1305-1323, 2011.
Lee, Y.W., B. Hennig, J. Yao, and M. Toborek. Methamphetamine induces AP-1 and NF-B binding and transactivation in human brain endothelial cells. J. Neurosci. Res. (in press), 2012
Pu H, Tian J, Andras IE, Hayashi K, Flora G, Hennig B, Toborek M. HIV-1 TAT protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK1/2 activation. J Cereb Blood Flow Metab (in press), 2012
Zheng Y, Morris A, Sunkara M, Toborek M, Hennig B. Epigallocatechin-gallate stimulates NF-E2-related factor and heme oxygenase-1 via caveolin-1 displacement. J Nutr Biochem (in press), 2012
Park M, Hennig B, Toborek M. Methamphetamine alters occludin expression via NADPH oxidase-induced oxidative insult and intact caveolae. J Cell Mol Med (in press), 2012
Chen L, Choi JJ, Choi YJ, Hennig B, Toborek M. HIV-1 Tat-induced cerebrovascular toxicity is enhanced in mice with amyloid deposits. Neurobiol Aging (in press), 2012
Choi W, Eum SY, Lee YW, Hennig B, Robertson LW, Toborek M. PCB 104-induced proinflammatory reactions in human vascular endothelial cells: relationship to cancer metastasis and atherogenesis. Toxicol.Sci. (in press), 2012
Andras, Ibolya E.; Pu, Hong; Tian, Jing; Deli, Maria A.; Nath, Avindra; Hennig, Bernhard; Toborek, Michal. Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells. Journal of Cerebral Blood Flow & Metabolism (J Cereb Blood Flow Metab). (in press), 2012