Vascular mimetics to study inflammation and atherosclerosis

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DESCRIPTION (provided by applicant): Visceral obesity is associated with high triglyceride rich lipoproteins (TGRL) and low HDL. These individuals typically suffer from metabolic syndrome and are at increased risk for atherosclerosis. Diets high in saturated fat lead to arterial plaque formation through binding and uptake of TGRL, which penetrate into the vascular wall and stimulate cytokine expression and recruitment of monocytes. We have developed an ex-vivo system that models these early inflammatory events in atherogenesis. The influence of a high-fat diet is mimicked by repetitively exposing aortic endothelium in culture to native postprandial TGRL that is freshly-isolated from human plasma. Our primary hypothesis is that native unmodified TGRL amplifies cytokine mediated inflammation via an LDL receptor initiated pathway that is distinct from that of oxidized lipoprotein and the scavenger receptor pathway. Endothelial dysfunction is associated with vascular regions of low shear stress and disturbed flow that are sites of lipid accumulation and monocyte recruitment, both of which accelerate the inflammatory axis of atherogenesis. A systems bioengineering approach is applied to study this process at the cell and molecular scale under defined shear stress as described in three Specific Aims: 1) To define how repetitive exposure of human aortic endothelial cells to TGRL primes for enhanced vascular inflammation and atherogenesis employing a vascular mimetic flow channel system. 2) To analyze the inflammatory events in atherogenesis at the level of gene transcription and protein expression by aortic endothelial cells under conditions of well defined fluid shear stress. 3) To identify the molecular mechanisms underlying monocyte recruitment to atherogenic endothelium in vascular mimetic flow channels. Our overall goal is to identify how dietary lipoproteins from healthy and metabolic syndrome subjects act as proinflammatory mediators in shifting the balance from healthy to atherogenic endothelium.Project Narrative: Few studies have focused on the earliest event in atherosclerosis when endothelium succumbs to hyperlipidemia and lowers its normal defenses to stave off inflammation. A significant outcome of the proposed studies would be to develop a lab on a chip that measures the inflammatory potential of an individual's lipids after a meal. This would reflect a person's metabolic profile and correlate with their propensity to develop atherosclerosis and heart disease.