The metabolic syndrome is increasingly prevalent in our society and represents a major risk forvascular disease. This syndrome is characterized by central obesity, insulin resistance, fasting andpost-prandial atherogenic dyslipidemia as well as a chronic pro-inflammatory state. Thus, chronicactivation of innate immunity and postprandial stress converge on the vasculature in the metabolicsyndrome.We use low-level human endotoxemia as a model to examine the impact of adiposity and metabolicsyndrome on vascular injury and atherogenic signaling in vivo. We have found that this modelprovides novel mechanistic insight into human pathophysiology in the metabolic syndrome. In thisSCCOR project we propose to extend this work by; (Specific Aim 1) performing a placebo controlledtrial of peroxisome proliferator-activated receptor alpha (Fenofibrate) and gamma (Rosiglitazone) agonists andNiacin (collaboration with Project by Rader); (Specific Aim 2) use of placebo-controlled acute highfatmeal provocation; and (Specific Aim 3) performing an evoked-phenotype pharmacogenetic studyon the endotoxin-mediated vascular injury response.In specific hypothesis-driven studies, we will determine the impact of drugs, diet and genes onendotoxin-related vascular injury pathways including; (a) cytokines and inflammatory molecules, (b)cyclooxygenases (COXs) and vasoactive prostaglandins (PGs), particularly PGD2 (collaborationwith Project by Fitzgerald), (c) oxidant stress (utilize the Biomarker Core (Blair), and (d) vasoactiveadipokines. Drug, diet and candidate gene related changes in leukocyte, monocyte and adiposegene expression will be integrated with plasma and urinary biomarker responses and will serve toprovide mechanistic insights that will complement cell and animal model studies across our SCCORapplication. Metabolic syndrome represents our major clinical focus because of the interplay ofmetabolic and inflammatory signals in the promotion of vascular injury and atherosclerosis in thissetting.
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