Response to retention hypothesis as a source of targets for arterial wall-directed therapies to prevent atherosclerosis: A critical review

The subendothelial retention of circulating lipoproteins on extracellular matrix proteins and proteoglycans is one of the earliest events in the development of atherosclerosis. Multiple factors, including the size, type, composition, surrounding pH, and chemical modifications to lipoproteins, influence the electrostatic interactions between relevant moieties of the apolipoproteins on lipoproteins and the glycosaminoglycans of proteoglycans. The length and chemical composition of glycosaminoglycan chains attached to proteoglycan core proteins determine the extent of initial lipoprotein binding and retention in the artery wall. The phenomena of hyperelongation of glycosaminoglycan chains is associated with initial lipid retention and later atherosclerotic plaque formation. This review includes a summary of the current literature surrounding cellular mechanisms leading to GAG chain modification and lipid retention and discusses potential therapeutic strategies to target lipoprotein:proteoglycan interactions to prevent the development and progression of atherosclerosis.