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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.
2010 Project Description
Complications of vascular diseases, including atherosclerosis, are the number one cause of death in the United States, and especially in Kentucky. Dysfunction of endothelial cells is a critical underlying cause of the pathology of atherosclerosis. Our work continues to focus on the hypothesis 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 phenolics), 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 wellbeing.
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.
Han SG, Eum SY, Toborek M, Smart E, Hennig B. Polychlorinated biphenyl-induced VCAM-1 expression is attenuated in aortic endothelial cells isolated from caveolin-1 deficient mice. Toxicol Appl Pharmacol 246(1-2):74-82, 2010.
Zhang B, Chen L, Swartz KR, Bruemmer D, Eum SY, Huang W, Seelbach M, Choi YJ, Hennig B, Toborek M. Deficiency of telomerase activity aggravates the blood-brain barrier disruption and neuroinflammatory responses in a model of experimental stroke. J Neurosci Res 88(13):2859-68, 2010.
Andras IE, Eum SY, Huang W, Zhong Y, Hennig B, Toborek M. HIV-1-induced amyloid beta accumulation in brain endothelial cells is attenuated by simvastatin. Mol Cell Neurosci, 43: 232-243, 2010.
Choi YJ, Arzuaga X, Kluemper CT, Toborek M, Hennig B. Quercetin blocks caveolae-dependent proinflammatory responses induced by co-planar PCBs. Environ Int 36(8):931-4, 2010.
Zhong Y, Hennig B, and Toborek M. Intact lipid rafts regulate HIV-1 Tat protein-induced activation of the Rho signaling and upregulation of p-glycoprotein in brain endothelial cells. J Cereb Blood Flow Metab 30(3):522-33, 2010.
Seelbach M, Chen L, Powell A, Choi YJ, Zhang B, Hennig B, Toborek M. Polychlorinated biphenyls disrupt the blood-brain barrier integrity and promote brain metastasis formation. Environ Health Perspect 118(4):479-84, 2010.
Zheng Y, Toborek M. Hennig B. Epigallocatechin gallate-mediated protection against tumor necrosis factor-α-induced monocyte chemoattractant protein-1 expression is heme oxygenase-1 dependent. Metabolism 59(10):1528-35, 2010.
Huang W, Rha GB, Chen L, Seelback MJ, Zhang B, Andras IA, Bruemmer D, Hennig B, Toborek M. Inhibition of telomerase activity alters tight junction protein expression and induces transendothelial passage of HIV-1-infected cells. Am J Physiol Heart Circ Physiol 298(4):H1136-45, 2010.
Majkova Z, Toborek M, Hennig B. The role of caveolae in endothelial cell dysfunction with a focus on nutrition and environmental toxicants. J Cell Mol Med 14(10):2359-70, 2010.
Choi YJ, Seelbach MJ, Pu H, Eum SY, Chen L, Zhang B, Hennig B, Toborek M. Polychlorinated biphenyls disrupt intestinal integrity via NADPH oxidase-induced alterations of tight junction protein expression. Environ Health Perspect 118(7):976-81, 2010.