The Role of High Density Lipoprotein Associated Protease Inhibitor Activity in Protection Against Atherosclerosis.

High density lipoproteins (HDL) have a well-established inverse correlation with the occurrence of cardiovascular disease. However, the functional activities of HDL which mediate this protection are not well understood. HDL are micelle-like complexes composed of lipids and an array of different proteins which confer specific functions to the HDL particles that carry them. Of more than 85 HDL-associated proteins over 20% have functions related to protease inhibition. The majority of these are members of the Serine Protease Inhibitor (SERPIN) family. This proposal will examine the structural interaction between the most abundant HDL-bound SERPIN, alpha-1-antitrypsin (A1AT), and HDL particles to evaluate the functional consequences of this interaction. Dr. Gordon will use individual particle electron tomography, a novel molecular imaging technique, to determine the structural details of the interaction between A1AT and HDL and to identify the region of the A1AT protein involved in binding. Using reconstituted HDL, enriched with A1AT, Dr. Gordon will investigate the mechanism of co-transport across the vascular endothelium in vitro and the capacity of these particles to reduce vascular protease activity and atherosclerosis in vivo. Additionally, a novel HDL-targeting small peptide mimetic of A1AT will be evaluated for its capacity to prevent atherosclerosis and to stabilize existing atherosclerotic plaque. These studies will provide novel tools for evaluating the role of protease activity in vascular disease and may reveal a novel approach for prevention of arterial thrombus formation and subsequent cardiovascular events, such as heart attack and stroke.