Vascular Inflammation and Atherosclerosis

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DESCRIPTION (provided by applicant): There is evidence that inflammation contributes at each stage in the development of clinically significant Atherosclerosis. Importantly, patients with elevated levels of circulating inflammatory markers such as C-reactive protein and ICAM-1 are at increased risk of cardiovascular events. This is especially true for the growing numbers of Type 2 diabetics and patients with the metabolic syndrome. The major hypothesis of this PPG proposal is that specific pro-inflammatory events in endothelial cells and vascular smooth muscle cells modulate the severity of atherosclerosis. Our approach is to identify and characterize signal transduction mechanisms that promote vascular inflammation. We are using combined analyses of regulation by transcription, post-transcriptional, and post-translational modifications. The candidate signal pathways include flow-mediated regulation of thioredoxin, PPAR-gamma, MCP-1, and cyclic nucleotide phosphodiesterases. Our goals are to prove that these candidate mechanisms modulate the development and progression of atherosclerosis in the LDL receptor deficient mouse. We believe that the PPG mechanism will facilitate these goals by fostering a vibrant and highly focused environment that will advance our understanding of signal transduction mechanisms in blood vessels. In addition, by creating histopathology and imaging cores the expertise necessary for the analysis of transgenic and knockout mouse models will be readily available. We anticipate that the interactions among investigators in the present proposal will provide new insights into the pathogenic roles of inflammation in atherosclerosis.