Aggressive therapy with lipid drugs has been shown to produce regression of coronary artery disease. Unfortunately, the bulk of the lipid in plaques, localized extracellularly, cannot be removed by current lipid drugs. A strategy for extracellular lipid removal by pharmacological means requires understanding the composition, structure and origin of the extracellular lipid. We have made the intriguing observation that liposome-like particles isolated from human atherosclerotic lesions are rich in apo A-I and apo C and contain excess SPM. We propose that these particles are lipolytic surface remnants of lipoproteins, produced either in the intimal space by undefined processes and/or in the plasma compartment as a product of normal lipolysis and then transcytosed into the intima. Supporting this hypothesis is the production of virtually identical apo A-I and apo C-containing and SPM-enriched liposome-like particles during in vitro lipolysis of VLDL in the presence of low levels of MDL; in the absence of HDL, little, if any, surface remnants separate from the VLDL core remnants. These in vitro-produced particles represent a complex between excess surface remnants and HDL; in the presence of high HDL the surface remnants are assimilate by HDL. This phenomenon can explain the clinical mystery of why HTG patients have low HDL; massive concentrations of surface remnants adsorb apo A-I or apo A-I-containing HDL into the VLDL remnant particles. Additionally, vesicular particles from plaques are-ken up by cultured macrophages more avidly than is acetylated LDL; HDL addition inhibits cholesterol loading. Based on these observations, we propose that one role of HDL is to assimilate the liposome-like particles: (a) in a mop-up fashion to remove them from the artery wall and/or (b) in a preventive fashion in the plasma compartment to prevent their transcytosis into the artery wall. We therefore suggest that the origin and fate of the extracellular lipid particles of atherosclerotic lesions may represent a major unsolved element essential to our understanding and control of the initiation and/or development of atherosclerosis. To pursue the origin and fate of the apo A-I and apo C- containing lipoproteins and SPM in atherosclerotic lesions, and the role of HDL in preventing their formation, we propose the following three specific aims: l) To test the hypothesis that specific HDL subspecies assimilate both excess surface remnants from TH-rich lipoproteins and liposome- like particles from atherosclerotic plaques. 2) To study the structure and composition of the liposome and lipoprotein-like particles in human atherosclerotic lesions as a function of plaque morphology. 3) To examine the interactions of liposome- and lipoprotein-like particles isolated from atherosclerotic plaques with cultured cells (macrophages and endothelial cells).
