Soluble heparin proteoglycans released from stimulated mast cells induce uptake of low density lipoproteins by macrophages via scavenger receptor-mediated phagocytosis.
Stimulation of rat serosal mast cells in vitro triggers exocytosis of secretory granules from their cytoplasm. Thereupon, the granules lose their perigranular membranes, and about 40% of the heparin proteoglycans and all of the chondroitin sulfate proteoglycans that they initially contained are released into the incubation medium. At physiologic ionic strength and calcium ion concentration, the solubilized heparin proteoglycans, but not the chondroitin sulfate proteoglycans, form insoluble complexes with the low density lipoproteins (LDL) present. We calculated that the heparin proteoglycans could bind approximately seven times their own mass (Mr about 1 x 10(6)) of LDL cholesterol. Using gold-labeled LDL, we observed massive phagocytosis of the heparin proteoglycan-LDL complexes by cultured mouse macrophages in vitro, which was inhibited by cytochalasin B. Uptake of LDL by mouse macrophages was 45-fold higher in the presence of solubilized heparin proteoglycans than in their absence, and continued unabated over a 72-h period, indicating that the uptake process was not under negative feedback control. Excess amounts of acetyl-LDL or polyinosinic acid inhibited the uptake of these insoluble heparin proteoglycan-LDL complexes, indicating that their phagocytosis was mediated by scavenger receptors of the acetyl-LDL receptor type. The experiments reveal the following pathophysiologic mechanism relevant to atherogenesis: stimulated mast cells secrete soluble heparin proteoglycans capable of forming insoluble complexes with LDL and thereby trigger uptake of LDL by macrophages through scavenger receptor-mediated phagocytosis.
Lindstedt
K A
KA
Wihuri Research Institute, Helsinki, Finland.
Kokkonen
J O
JO
Kovanen
P T
PT
D000818:Animals; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000378:metabolism; D005089:Exocytosis; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000648:ultrastructure; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008854:Microscopy, Electron; D010587:Phagocytosis; D011509:Proteoglycans / Q000378:metabolism*; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism; D012995:Solubility
D008077:Lipoproteins, LDL; D011509:Proteoglycans; D011973:Receptors, LDL; C036090:heparin proteoglycan; D006493:Heparin