Identifying novel atheroprotective mechanisms

Clemson University, Clemson SC

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Atherosclerosis is a disease caused by cholesterol accumulation in the arterial intima. Since atherosclerosis causes heart attacks and strokes, this disease is considered to be the leading cause of death globally. Hence, finding more effective treatments for atherosclerosis may reduce deaths that are caused by heart attacks and strokes. Increasing the removal of cholesterol from arterial intimal cells may be a possible approach for treating atherosclerosis. One type of arterial intimal cell that has been proposed to greatly influence atherosclerosis progression is vascular smooth muscle cells. These types of cells can migrate from the arterial media into the intima and begin internalizing intimal cholesterol. However, once vascular smooth muscle cells become cholesterol-filled, it is thought that they lose the capacity to remove excess cholesterol through downregulation of the ABC- transporters, ABCA1 and ABCG1. These two transporters remove intracellular cholesterol from cells by participating in cholesterol efflux. ABCA1 and ABCG1 do not efflux cholesterol identically though, as they interact with various cholesterol acceptors differently to mediate cellular cholesterol efflux. Furthermore, it is not currently known whether ABCA1 and/or ABCG1 expression in vascular smooth muscle cells is atheroprotective, and if increasing expression of these transporters may protect against atherosclerosis. The goal of this proposal is to test whether ABCA1 and ABCG1 expression in vascular smooth muscle cells is atheroprotective. This proposal has two Aims, with both Aims utilizing cell culture systems and atherogenic mice. One Aim will robustly analyze the potential atheroprotective impact of ABCA1 expression in vascular smooth muscle cells by using vascular smooth muscle cell-specific overexpression and knockout models. The second Aim will rigorously assess the potential atheroprotective impact of vascular smooth muscle cell ABCG1 expression by employing models that are either ABCG1 deficient or overexpress ABCG1. The long-term objective of this proposal is to discover vascular smooth muscle cell ABC-transporter expression as being atheroprotective. Succeeding in both Aims would accomplish this objective and demonstrate proof-of- principle that increasing ABCA1 and ABCG1 expression precisely in vascular smooth muscle cells may be a novel strategy for treating atherosclerosis.