Mast Cells in Atherogenesis: A Model for Studying Proteolytic Modification of Low and High Density Lipoproteins

Immunohistochemical observations on human atherosclerotic lesions have revealed that the lesions contain, not only foam cells, but also mast cells. Studies taking advantage of in vitro and in vivo models that use rodent mast cells and human lipoproteins have disclosed a series of metabolic events by which mast cells can induce the formation of foam cells. The mast cells are filled with cytoplasmic secretory granules containing histamine, heparin proteoglycans, and neutral proteases. When activated, mast cells degranulate, i.e. they expel their granules and in this way influence the metabolism of lipoproteins in their vicinity. In the extracellular fluid, histamine is released from the exocytosed granules, but the heparin proteoglycans and neutral proteases (notably the chymotryptic enzyme chymase) remain tightly bound together in the form of granule remnants. Of the three granule remnant components, (1) histamine increases endothelial permeability, thereby enhancing transendothelial transport of low-density lipoproteins (LDL) into the tissues; (2) the heparin proteoglycans bind LDL; and (3) the chymase degrades the apolipoprotein B-100 component of the granule remnant-bound LDL. Such proteolytically modified LDL particles are unstable and fuse into larger lipid droplets (up to 100 LDL per droplet), and so allow the granule remnants to bind new LDL particles and to increase their maximal LDL binding capacity. Ultimately, macrophages or smooth muscle cells phagocytose the granule remnants loaded with fused LDL particles, degrade them within phagosomes, and become converted into typical foam cells. The chymase also attacks the HDL3 particles, effectively proteolyzing their apolipoprotein components, and thereby reducing the ability of HDL to induce efflux of cholesterol from the foam cells. Notably, the high-affinity component of cholesterol efflux is blocked, this being due to specific proteolytic depletion of the small apolipoprotein A-I- and A-IV-containing particles present in plasma. Taken together, experimental work carried out with rodent mast cells and immunohistochemical studies on human arterial samples suggest that stimulated mast cells can accelerate foam cell formation both by promoting the uptake of LDL cholesterol and by inhibiting release of cellular cholesterol, i.e. the initial step of reverse cholesterol transport.