Metabolism of LDL in mast cells recovering from degranulation. Description of a novel intracellular pathway leading to proteolytic modification of the lipoprotein.

Abstract

Rat serosal mast cells contain cytoplasmic secretory granules composed of a proteoglycan matrix in which histamine and neutral proteases are embedded. On stimulation, these granules are exocytosed, but some of them remain in the degranulation channels where on exposure to the extracellular fluid, they lose their histamine and a fraction of their proteoglycans. In vitro, such granule remnants efficiently bind low density lipoprotein (LDL) present in the incubation medium. After a lag period of about 10 minutes, the granule remnants, still within the channels and coated with LDL particles, are internalized by the parent mast cells. During subsequent recovery from degranulation, the apolipoprotein B of the intracellularly located remnant-bound LDL becomes efficiently (up to 70%) degraded by the proteolytic enzymes of the granule remnants. Since the granule remnants lack cholesteryl esterase activity, no LDL cholesterol is made available for cellular nutrition. Instead, selective proteolytic degradation of the bound LDL leads to formation of LDL particles enlarged by fusion on the granule remnant surface. In response to restimulation of the mast cells, about 50% of the fused LDL particles are exocytosed with the granule remnants. Of these, about one in five are expelled into the incubation medium. The granule remnants that again remain in the degranulation channels bind and internalize more LDL. This "round trip" of LDL in mast cells exposed to repeated stimulation constitutes a hitherto-unknown intracellular pathway for modification of LDL. T he cholesterol found in atherosclerotic lesions is mainly derived from low density lipoproteins (LDLs) that have penetrated into the intima, the inner layer of the arterial wall.1 Native LDLs are not effectively metabolized by macrophages, which are the precursors of most of the cholesteryl ester-filled foam cells found in atherosclerotic lesions.2 Therefore, it has been postulated that LDL must be modified in the intima to be recognized and taken up by macrophages. 3 -3 One cell type that is present in atherosclerotic lesions in both animals and humans 6 -7 and that is capable of modifying LDL and carrying it into macrophages 8 is the mast cell. The most characteristic morphological feature of mast cells is their cytoplasmic secretory granules. These organelles are thought to represent specialized primary lysosomes. 9 The granules are composed of a proteoglycan matrix in which are embedded the other components, such as histamine and neutral proteases. The matrix is composed of heparin proteoglycans and oversulfated chondroitin sulfate proteoglycans in various proportions, depending on the particular subpopulation of mast cells. 10 The neutral proteases of rat serosal mast cells, the model in our studies, consist of two proteases with complementary specificities: a chyFrom the Wihuri Research Institute, Helsinki.

Deranged aortic intima‐media thickness, plasma triglycerides and granulopoiesis in Sl/Sld mice

“…3 Á 7 Although mast cells are primarily known for their role in the development of hypersensitivity reactions, strong evidence implicates this cell type in the progression of atherosclerosis. The presence of an increased number of mast cells in atherosclerotic lesions, 8 Á 12 atheromas, 13 and in the adventitia of coronary arteries with plaques 14,15 supports this concept. In addition, thrombus formation is associated with an increase in the number of mast cells in the arterial wall.…”

“…To this effect mast cell chymase and carboxypeptidase A are known to degrade LDL. 13,19 Again, it is of interest that the serum cholesterol levels were unaltered in the mast cell-deficient Sl/Sl d genotypes. This finding together with the increased triglyceride levels in Sl/Sl d mice suggest that deficiency of mast cell proteases, which are known to degrade and augment triglyceride uptake by macrophages, may be responsible for the hypertriglycer-idimia.…”

“…In the subendothelial space, modified LDL can act as a chemoattractant for monocytes that adhere to the endothelium, migrate into subendothelial space and become macrophages that transform into foam cells by uptake of altered LDL. Mast cell granule proteases have been shown to modify LDL and enhance their uptake by macrophages with transformation to foam cells, 13,19 suggesting a role for the mast cell in lipidrelated atherosclerosis.…”