Modified low density lipoprotein isolated from atherosclerotic lesions does not cause lipid accumulation in aortic smooth muscle cells.
Foam cells in atherosclerotic lesions are derived not only from blood monocytes but also from smooth muscle cells (SMC). To better understand the mechanisms by which SMC may become lipid-laden, we have studied the catabolism by cultured rabbit aortic SMC of LDL derived from atherosclerotic lesions (A-LDL) previously shown to be chemically modified. A-LDL was isolated either from homogenates of atherosclerotic plaques in human aortas by affinity chromatography and gel filtration, or from nonhomogenized extracts of plaque minces by ultracentrifugation and gel filtration. Internalization of A-LDL by SMC or fibroblasts appeared to be mediated primarily via the LDL receptor since: 1) either unlabeled LDL or A-LDL could inhibit the degradation of 125I-labeled A-LDL or of 125I-labeled LDL, 2) the uptake of both A-LDL and LDL, as estimated by their abilities to stimulate cholesterol esterification, was reduced in cells in which LDL receptor expression was down-regulated; and 3) the uptake of both [3H]cholesteryl ether-labeled A-LDL and LDL by normal fibroblasts was significant and could be inhibited by excess LDL, but was negligible in receptor-negative fibroblasts. At saturating concentrations of lipoproteins, maximum cholesterol esterification in SMC was greater for LDL than for A-LDL. Over a 48-h incubation, A-LDL, like LDL, was unable to induce cellular cholesteryl ester accumulation. Cross-competition studies suggested that either the affinity of A-LDL for the LDL receptor was less than that of LDL, or that some particles in A-LDL are not internalized by SMC. The latter alternative was supported by the observations that some A-LDL particles had undergone aggregation, especially at high concentrations, and that aggregated forms of A-LDL or plasma LDL failed to be internalized and degraded by SMC. Collectively, these results are consistent with recognition of some of the A-LDL particles by the LDL receptor, but also suggest that, at least under in vitro conditions, A-LDL is unlikely to induce lipid accumulation in SMC resulting in SMC-derived foam cells.
Hoff
H F
HF
Department of Vascular Cell Biology and Atheroslcerosis Research, Cleveland Clinic Foundation, OH 44195.
Pepin
J M
JM
Morton
R E
RE
D000328:Adult; D000368:Aged; D000818:Animals; D001011:Aorta / Q000737:chemistry; D001161:Arteriosclerosis / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D002846:Chromatography, Affinity; D002850:Chromatography, Gel; D004951:Esterification; D006801:Humans; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000302:isolation & purification / Q000378:metabolism*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D011817:Rabbits
D002788:Cholesterol Esters; D008077:Lipoproteins, LDL