Grant: Collaborative Research and Development Grants

Despite advances in treatment and prevention, complications of atherosclerosis, including coronary heart disease and stroke, remain the leading cause of mortality in the Western world. Atherosclerosis is now widely regarded as a chronic inflammatory disease of the vascular wall, initiated by the aggregation of modified, usually oxidized, low-density lipoproteins (oxLDL) also called ""bad cholesterol"". Macrophages are thought to be key to the genesis and progression of atherosclerosis. When their surface receptors engage oxLDL deposited onto the subendothelial matrix, macrophages generate inflammatory mediators. Gradually, the macrophages take up and store inordinate amounts of cholesterol, becoming ""foam cells"" that have altered immune responsiveness. These abnormalities lead to the formation of plaque and ultimately to its rupture, which causes the thrombosis responsible for infarction and stroke. Recent results from our laboratories and others indicate that large particles of oxLDL are slowly engulfed by macrophages in a protracted process that stimulate macropages into an abnormal inflamatory response. This abnormality could contribute to the development of a localized chronic inflammatory response. The development of atherosclerosis could be lessened by minimizing subendothelial inflammation, and by preventing the further accumulation of cholesterol in macrophages. This can, in theory, be accomplished by neutralizing the inflammatory reaction of CD36 to oxLDL aggregates that contributes prominently to the development of atherosclerosis. However, under normal circumstances, the accumulation and aggregation of oxLDL is prevented by its active endocytosis and metabolism, a process also mediated by CD36 and other scavenger receptors. A suitable strategy would be to enable macrophages to clear dissolved oxLDL, while minimizing the inflammatory response to the large aggregates of oxLDL in the intima of the arteries. This approach requires the ability to separate the normal endocytic pathway that occurs on the nano particle scale from the inflammatory phagocytic functions of scavenger receptors that occurs on the micro particle scale.