The overall goal of this proposal is to study the interactions of triglyceride-rich lipoproteins(TGRL), lipolysis of TGRL, and HDL with the artery wall.
The aims of this proposal are:
Aim 1. Test the hypothesis that lipolysis of TGRL increases the accumulation of both surface and core lipid components of TGRL in the artery wall as a result of an increase in endothelial layer permeability. We will determine before and after lipolysis: (1) endothelial layer permeability to fluorescently labeled dextran, (2) accumulation of TGRL remnant particles, and (3) localization of TGRL surface and core lipid in atherosclerotic and nonatherosclerotic mouse carotid arteries.
Aim 2. Test the hypotheses that (a) HDL accepts lipolysis products that injure endothelium and thus reduces endothelial layer permeability. (b) HDL removes lipid from the artery wall derived from lipolysis of TGRL. We will (1) measure permeability to dextran following lipolysis in the presence and absence of HDL, and (2) load the vessel wall with fluorescently labeled lipolysis products and measure their removal by HDL.
Aim 3. Test the hypothesis that apoE derived from arterial macrophages competitively inhibits binding of apoE-associated lipoproteins to glycosaminoglycans, thereby reducing lipoprotein retention in the artery wall. We will use apoE-deficient mice to determine the vascular retention of fluorescently labeled lipid emulsions (1) with and without associated apoE, and (2) in the presence and absence of macrophage-derived apoE following bone marrow or aortic transplantation. Further studies are needed to investigate the interactions of lipoproteins with the artery wall comprehensively and precisely. Using new approaches, our research will define mechanisms of TGRL-mediated flux in the artery wall and atherosclerosis formation and prevention. Our work will provide insight into the pathophysiology of atherosclerosis in patients with hypertriglyceridemia.
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