Phagocytosis of mast cell granule remnant-bound LDL by smooth muscle cells of synthetic phenotype: a scavenger receptor-mediated process that effectively stimulates cytoplasmic cholesteryl ester synthesis.
Mast cell granule remnants contain heparin proteoglycans and bind low density lipoproteins (LDL). Phagocytosis of such LDL-coated remnants by smooth muscle cells of synthetic phenotype (s-SMC) leads to cellular accumulation of LDL-derived cholesteryl esters (Wang et al. 1995. Arterioscler. Thromb. Vasc. Biol. 15: 801-810). In the present study, we investigated the pathway by which granule remnants mediate the uptake of LDL by s-SMC and the effect of the remnants on the metabolism of LDL-derived cholesteryl esters in these cells. In vitro, the scavenger receptor ligands polyinosinic acid, acetylated LDL (AcLDL), and oxidized LDL (OxLDL) each inhibited the uptake of granule remnant-bound LDL maximally by 50-60%. When AcLDL and OxLDL were added as a mixture, uptake was totally inhibited. Conversely, the granule remnants inhibited the binding of AcLDL to s-SMC. We also found that granule remnants did not inhibit the lysosomal hydrolysis of LDL-derived cholesteryl esters in s-SMC. When s-SMC were incubated with LDL in the presence of granule remnants, the cellular contents of cholesteryl linoleate and cholesteryl oleate increased. These increases were retarded when an inhibitor of acyl-CoA:cholesterol acyl-transferase (ACAT) was present, showing that the cholesteryl ester accumulation in the s-SMC was a cytoplasmic process due to reesterification of LDL-derived cholesterol and fatty acids. In summary, exocytosed mast cell granule remnants carry LDL into s-SMC by scavenger receptor-mediated phagocytosis, and induce formation of typical foam cells, filled with cytoplasmic cholesteryl ester droplets.
Wihuri Research Institute, Helsinki, Finland.
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Y
Wang
K A
KA
Lindstedt
P T
PT
Kovanen
D000818:Animals; D001011:Aorta / Q000378:metabolism; D002788:Cholesterol Esters / Q000096:biosynthesis*; D003594:Cytoplasmic Granules / Q000378:metabolism; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D008407:Mast Cells / Q000648:ultrastructure*; D008565:Membrane Proteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D010587:Phagocytosis; D011069:Poly I / Q000494:pharmacology; D011817:Rabbits; D011971:Receptors, Immunologic / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein; D011069:Poly I