Scavenger receptor-independent stimulation of cholesterol esterification in macrophages by low density lipoprotein extracted from human aortic intima.

Abstract

There is a growing body of evidence that suggests that modification of low density lipoprotein (LDL) in the artery wall may contribute to atherogenesis. A number of physiologically plausible modifications have been studied in vitro, including oxidation, aggregation, formation of complexes with giycosaininoglycans, and generation of LDL-immune complexes. Several studies of the properties of LDL extracted from the aortic intima have been published, but these indicate disagreement about both the nature and the extent of modification of LDL in the artery wall. The objectives of the present study were to determine the nature and extent of modification of LDL extracted from both normal and diseased human aortic intimas and to correlate this with the rate of LDL uptake in cultured cells. Analyses were performed on LDLs isolated from aortic intimas obtained at autopsy or at the time of organ harvest from 33 subjects. LDL from normal intima showed no clear evidence of oxidation but had slightly increased electrophoretic mobility compared with native plasma LDL, whereas LDL from plaques or fatty streaks exhibited variable but usually modest signs of oxidative change. Aortic LDL was more rapidly degraded by cultured macrophages than was plasma LDL and resulted in a greater stimulation of cholesterol esterification. The degree of stimulation of cholesterol esterification was correlated with the extent of modification of LDL as reflected by the degree of apolipoprotein B fragmentation. However, in all aortic LDLs the extent of oxidative change, as assessed by electrophoretic mobility or other physical parameters, was less than that required for scavenger receptor-mediated uptake. In all cases where sufficient amounts of LDL were recovered to permit degradation experiments, the uptake of aortic LDL was nonsaturable and could not be inhibited by polyinosinic acid or acetylated LDL. Chromatography on Sepharose CL-4B showed that most LDLs isolated from plaque contained a fraction that eluted in the void volume, and the size of this void peak correlated well with the stimulation of cholesterol esterification. Electron microscopy showed that the high-molecular-weight fraction contained several different types of aggregates. Some appeared to be clusters of LDL-size particles, but large vesicular structures with numerous adherent LDL particles as well as lipid droplets were also identified. These results indicate that the accelerated uptake by macrophages of LDL isolated from the arterial intima can largely be attributed to phagocytosis of LDL-containing aggregates. Findings consistent with oxidative modiflcation were found in LDL isolated from atherosclerotic plaque, and although this was insufficient to cause uptake via the scavenger receptor pathway, it could have contributed to aggregation. Other mechanisms, such as formation of LDL-immune complexes or interaction of LDL with matrix substances or vesicular structures, probably also contribute to LDL aggregation in the arterial intima. ( Received August 20,1991; revision accepted...

Enhanced Cholesterol Efflux by Tyrosyl Radical-oxidized High Density Lipoprotein Is Mediated by Apolipoprotein AI-AII Heterodimers

“…We have found ultracentrifugally isolated HDL to be more susceptible to tyrosyl radical oxidation than LDL. 3 We have also found recently that activated human monocytes and neutrophils can oxidize HDL by the myeloperoxidase-dependent generation of tyrosyl radical (50). This phagocyte-modified HDL exhibits a pattern of apoprotein cross-linking and enhanced cholesterol efflux capacity identical to that seen in tyrosylated HDL generated in vitro.…”

“…Low density lipoprotein (LDL) 1 particles containing modifications consistent with in vivo oxidation have been isolated from human atheromatous lesions (2)(3)(4)(5). Numerous potential mechanisms for the oxidation of lipoproteins in vivo have been proposed (6).…”

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

“…10,36 This conclusion is consistent with the finding that the extent of oxidative change to aortic LDL, as assessed by electrophoretic mobility or other physical parameters, is less than that required for scavenger receptor-mediated uptake. 37 Second, our observation has potential implications for the formation of both minimally modified LDL and isoprostanes. Oxovaleroyl, glutaroyl, and epoxyisoprostane (the three active moieties identified in minimally modified LDL generated in vitro 38 ) and isoprostanes are secondary lipid oxidation products.…”

Dehydroascorbic acid prevents apoptosis induced by oxidized low‐density lipoprotein in human monocyte‐derived macrophages

“…Human atherosclerotic plaques contain modified LDL C-supplemented culture medium. Serum-supplemented culture medium (5%), however, always completely inhibited OxLDL-that share many properties of Cu 2ϩ -OxLDL [12, 45,46]. Suarna et al reported that plaques not only contain oxidized lipids but induced apoptosis even though DHAA levels in the medium most likely did not exceeded 1 µM, too low a concentration for relatively large amounts of vitamin E and C as well.…”