Stimulation of cholesteryl ester synthesis in macrophages by extracts of atherosclerotic human aortas and complexes of albumin/cholesteryl esters.

Abstract

This research was supported by research Grants HL 20948 and NS 09287 from the National Institutes of Health. Dr. Hoff was an Established Investigator of the American Heart Association.Address This sequence of uptake, hydrolysis, and reesterification occurs when macrophages are incubated with LDL that has been rendered polyanionic by chemical derivitization, such as by maleylation 57 or by reaction with malondialdehyde, 7 " 9 in addition to acetylation. 5 ' 9 A similar uptake can be triggered by allowing LDL to form complexes with certain sulfated polysaccharides, such as dextran sulfate, which bind to the macrophage surface. 10 The only unmodified plasma lipoproteins known to be recognized directly by mouse peritoneal macrophages are the ^-migrating very low density lipoproteins (fr-VLDL) that accumulate in the plasma of cholesterol-fed animals."• 12 The /8-VLDL bind to a discrete class of macrophage receptors that are distinct from the ones that bind polyanions. The intracellular metabolism of /3-VLDL is the same as that of acetyl-LDL, i.e., lysosomal hydrolysis followed by cytoplasmic re-esterification. These studies raise the question as to whether any of the cholesteryl ester present in human atherosclerotic plaque is in a form recognized and taken up by macrophages. Hoff et al. 13 and Hollander et al.14 have shown that cholesterol-rich particles can be extracted from human atherosclerotic plaque after vigorous homogenization. Some of this extracted cholesterol is found in the form of large lipid/protein complexes that appear in the void volume of a Bio-Gel A-150 m column. Another portion of the cholesterol is found in particles in the molecular weight range of 3 X 10 6 as determined by gel filtration and electron microscopy (Gaubatz and Hoff, unpublished data). 13 These particles, which are about the same size as plasma LDL, are reactive with an antibody directed against apoprotein B (apo-B), the major protein component of plasma LDL. By sodium dodecyl sulfate polyacrylamide gel electrophoresis, the protein component of these aortic LDL-like particles migrates similarly to apo-B.13 In contrast to plasma LDL, these aortic particles have an enhanced mobility on agarose gel electrophoresis, suggesting an increased negative charge (Gaubatz and Hoff, unpublished data). '14 Woodard et al. 18 and Srinivasan et al. 19have isolated lipoprotein/glycosaminoglycan complexes from human atheroma. These complexes are excluded in the void volume of a BioGel A-50 m column and float in the ultracentrifuge in the density range of 1.006-1.063 g/ml. 19Our current studies were undertaken to determine whether any of the cholesteryl ester/protein complexes extracted from human aortas are taken up efficiently by mouse peritoneal macrophages. As an index of uptake, we measured the ability of the aortic extracts to increase the rate at which the macrophages incorporate [ 11 ' 12 The current results show that the cholesteryl ester of aortic extracts is in a form that is susceptible to rapid uptake by macrophages. Rapid uptake is obse...

Scavenger receptor-mediated recognition of maleyl bovine plasma albumin and the demaleylated protein in human monocyte macrophages.

“…Our studies indicate that such a cluster may be provided by the amino acids of bovine plasma albumin. Support for this proposal is derived from earlier studies conducted by Goldstein et al (11). These investigators demonstrated that coacervates of bovine plasma albumin and cholesteryl ester formed by sonication were recognized in part by the scavenger receptor of murine peritoneal macrophages.…”

“…Several other cholesteryl ester-rich lipoprotein complexes have been identified that bind to the scavenger receptor of macrophages and promote the intracellular accumulation of cholesteryl esters. These include LDL modified by malondialdehyde (6,7), diketene (8), or endothelial cells (9,10); particulate complexes of bovine serum albumin with cholesteryl ester (11); and lipid-protein particles extracted from human atherosclerotic aortas (11).…”

Unique Cellular Events Occurring during the Initial Interaction of Macrophages with Matrix-retained or Methylated Aggregated Low Density Lipoprotein (LDL)

“…Nonetheless, it is possible that this technique would not be able to discern a subpopulation of particles with a relatively modest enrichment of CE, and so this possibility must still be formally considered. In this regard, it is well documented that CE-rich particles exist in atherosclerotic lesions and can lead to CE accumulation in macrophages (67)(68)(69).…”

Phagocytosis of lipase-aggregated low density lipoprotein promotes macrophage foam cell formation. Sequential morphological and biochemical events.

“…Human atherosclerotic lesions contain lipoproteinlike particles that have been postulated to promote macrophage foam cell formation, 34 and several mechanisms modify LDL to a highly atherogenic lipoprotein in vitro. 1 " 5 -7 -9 - 15 Certain of these pathways may generate particulate lipoprotein.…”