Search PubMed⌕ Search

Biomedical subjects

M Aviram

Publications and source records attributed to M Aviram.

At least 127 records · Page 7Linked to original sources
PubMed1994

Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein receptor activity in macrophages: in vitro and in vivo studies.

1. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) inhibitor, is a highly selective inhibitor of hepatic cholesterol synthesis. We studied the in vivo and in vitro effects of pravastatin on macrophage cholesterol metabolism. 2. The effects of incubating pravastatin with human monocyte derived macrophages (HMDM), mouse peritoneal macrophages (MPM) and a J-774 A.1 macrophage-like cell line, on macrophage cholesterol synthesis, cellular degradation of native low density lipoprotein (LDL) and modified LDL, cholesterol efflux from these cells and the cholesterol esterification rate were determined. 3. Pravastatin was administered either as one 40 mg dose or 40 mg daily for 8 weeks to normocholesterolaemic and hypercholesterolaemic individuals. The effects on cholesterol synthesis and degradation in monocytes derived from these subjects were studied. 4. In vitro, pravastatin resulted in a dose-dependent inhibition of macrophage cholesterol synthesis. Cellular degradation of native LDL increased by 119% in the presence of 0.1 mg ml-1 pravastatin. Degradation of both acetyl LDL and oxidized LDL was unaffected. Small concentrations of pravastatin (up to 0.19 micrograms ml-1) increased the cellular cholesterol esterification rate after incubation with LDL, but higher concentrations resulted in an inhibition of the esterification. 5. Single dose pravastatin administration caused a reduction in cholesterol synthesis by the subjects own HMDM by 62% and 47% in normocholesterolaemic and hypercholesterolaemic individuals, respectively. Chronic administration resulted in a 55% inhibition of cholesterol synthesis and a 57% increase in LDL degradation. 6. The results indicate that the selective uptake of pravastatin shown for hepatocytes can be extended to macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Effect of dietary supplementation of red or white wine on human blood chemistry, hematology and coagulation: favorable effect of red wine on plasma high-density lipoprotein.

Twenty healthy males were divided into two groups: 10 subjects were supplemented for 2 weeks with 400 ml of red wine (11% alcohol) per day and the other 10 subjects were given 400 ml of white wine (11% alcohol) per day for a similar period. Blood samples were drawn prior to wine supplementation, after 1 week and at the end of the study. No significant effects were found on plasma concentrations of urea, creatinine, bilirubin, creatine kinase, amylase, blood cell counts, platelet counts and platelet aggregation. Both red- and white-wine supplementation resulted in a transient minor reduction in plasma glucose concentration and in a minor elevation in blood coagulation properties such as prothrombin time and partial thromboplastin time. Red (but not white) wine resulted in an 11 and 26% increment in plasma triglyceride concentrations after 1 and 2 weeks of supplementation, respectively. Plasma cholesterol, as well as very-low- and low-density-lipoprotein levels did not change during the 2 weeks of red- or white-wine supplementation. The most impressive effect of red-wine intake was a significant (p < 0.01) increase in plasma high-density lipoprotein (HDL) cholesterol and in plasma apolipoprotein A-I concentrations by up to 26 and 12%, respectively. These effects were not observed after the intake of white wine. We conclude that the major effect of red-wine supplementation (about 40 g of alcohol per day for a period of 2 weeks) was a significant increase in plasma HDL concentration which may contribute to the reduced risk for cardiovascular diseases observed in red-wine drinkers.

Adult↗
PubMed1994

Macrophage-mediated oxidation of extracellular low density lipoprotein requires an initial binding of the lipoprotein to its receptor.

Cells of the arterial wall including macrophages were shown to oxidize low density lipoprotein (LDL) in vitro. Upon incubation of LDL with J-774.A1 macrophage-like cell line for 18 h in the presence of 1 microM CuSO4, extensive macrophage-mediated oxidation of the LDL fatty acids and cholesterol moieties was demonstrated. Similar results were found with mouse peritoneal macrophages or human monocyte-derived macrophages. Several lines of evidence suggest that LDL binding to the LDL receptor on macrophages is required for the cell-mediated oxidation of LDL. 1) Incubation of the cells in the presence of monoclonal antibody to the LDL receptor (IgG-C7), substantially inhibited lipoprotein oxidation. 2) Pretreatment of LDL with monoclonal antibodies to the LDL receptor binding domains on the LDL apoB-100 (mAbs B1B6 and B1B3) inhibited cell-mediated oxidation of LDL by 52-95%. 3) Down-regulation of the macrophage LDL receptors (by preloading the cells with cholesterol) reduced LDL oxidation by 42%. 4) Up-regulation of the LDL receptor (by macrophage incubation in serum-free medium) was associated with 80% elevation in LDL oxidation. 5) Macrophage activation with lipopolysaccharide up-regulated the LDL receptors and was associated with up twofold increase LDL oxidation. 6) Human monocyte-derived macrophages from a patient with homozygous familial hypercholesterolemia, which lack the LDL receptor, failed to oxidize the LDL. 7) On using acetylated LDL or methylated LDL, which do not bind to the LDL receptor, macrophage-mediated oxidation of the lipoprotein did not occur. The binding of LDL to the macrophage LDL receptor under oxidative stress induced the oxidation of extracellular unbound LDL as demonstrated by cell-mediated lipid peroxidation of mAb B1B6-treated LDL by cells that were preincubated with native LDL. Furthermore, macrophage conditioned medium (MCM) that was obtained after 5 h of cells preincubation with native LDL under oxidative stress (1 microM CuSO4), followed by lipoprotein removal and a further 18 h of cell incubation (but not MCM that was similarly obtained without cell preincubation with LDL), was found to contain oxidized linoleic and arachidonic acids and was able to induce LDL lipids peroxidation. In conclusion, macrophage-mediated oxidation of LDL requires an initial binding of the lipoprotein to the LDL receptor on the cell surface under oxidative stress. This interaction leads to the formation and release of cellular oxidized polyunsaturated fatty acids that can oxidize the LDL molecule extracellularly.

Acetylation↗
PubMed1994

Involvement of second messengers in lipopolysaccharide stimulation of low density lipoprotein uptake by macrophages.

Macrophage degradation of low density lipoprotein (LDL) was shown to be increased in lipopolysaccharide (LPS)-stimulated cells. The involvement of second messengers in this phenomenon was studied. Preincubation of J-774A.1 macrophages with the protein kinase C (PKC) inhibitors D-sphingosine or staurosporine did not significantly affect the stimulatory action of LPS. Similarly, J-774A.1 macrophage-like cell line, incubation with 1,2-dioleoyl-sn-glycerol had no effect on cellular degradation of LDL. However, preincubation of J-774A.1 macrophages with dibutyryl cyclic adenosine monophosphate (50 microM dB-cAMP) led to a 51% increase in the cellular degradation of LDL. Analysis of cAMP content in LPS-stimulated cells revealed a 59% elevation in its cellular content in comparison to non-stimulated cells. Our results suggest that LPS stimulation of macrophage uptake of LDL occurs via the cAMP pathway and not via PKC activation. These results may contribute to understanding of the mechanism by which activated macrophages accumulate cholesterol.

Alkaloids↗
PubMed1994

Oxidized low density lipoprotein leads to macrophage accumulation of unesterified cholesterol as a result of lysosomal trapping of the lipoprotein hydrolyzed cholesteryl ester.

The early atherosclerotic lesion is comprised of foam cell macrophages filled with cholesteryl ester (CE), unesterified cholesterol (UC), and cholesterol oxides. Upon incubation of macrophages with oxidized low density lipoprotein (Ox-LDL), they accumulate UC rather than CE, which was shown to accumulate after incubation of cells with acetylated LDL (Ac-LDL). Using lipoproteins that were doubly labeled in their CE as well as in their protein moieties, we have demonstrated that lysosomal hydrolysis of the Ox-LDL CE was similar to the hydrolysis of the CE in Ac-LDL or native LDL whereas, as shown previously, a markedly impaired degradation of the protein moiety of Ox-LDL was observed. Cell fractionation revealed that the UC was derived from the hydrolyzed CE in Ox-LDL and was trapped in the macrophage lysosomal fraction, whereas in cells incubated with Ac-LDL, the lipoprotein UC was rapidly transported to the microsomal and cytosolic compartments. Lysosomal accumulation of Ox-LDL-derived UC could be related to the effect of the oxysterols in Ox-LDL, as oxidation of Ac-LDL or incubation of macrophages with Ac-LDL in the presence of oxysterols, in comparison to cell incubation with Ac-LDL, resulted in lysosomal accumulation of unesterified cholesterol. As a consequence of lysosomal trapping of Ox-LDL-derived UC, its availability to esterification was markedly impaired (by 6-fold), in comparison to the cholesterol esterification rate of Ac-LDL-derived UC. However, when the cholesterol esterification was expressed per lysosomal released UC, cellular cholesterol esterification rate of Ox-LDL-derived UC was found to be similar to that of Ac-LDL-derived UC. High density lipoprotein (HDL)-mediated efflux of the Ox-LDL-derived cholesterol from macrophages was similar to that found for Ac-LDL-derived cholesterol after 24 h of cell incubation with HDL3. Major defects in the cellular metabolism of Ox-LDL-derived 7-ketocholesterol were also found and could be related to its lysosomal trapping (together with the UC), its limited capacity to be esterified, and a 40% reduction in its HDL-mediated efflux from macrophages, in comparison to the efflux of the Ox-LDL-derived UC. We conclude that upon incubation of macrophages with Ox-LDL, lysosomal hydrolysis of the lipoprotein CE is not impaired but cellular accumulation of the Ox-LDL-derived UC occurs as a result of trapping of the hydrolyzed CE in the macrophage lysosomal compartment which may be related to the effect of oxysterols in Ox-LDL.

Animals↗
PubMed1993

Modified forms of low density lipoprotein and atherosclerosis.

Modified forms of low density lipoprotein (LDL) are associated with increased atherogenicity. Modified LDL, in comparison with native LDL, demonstrates enhanced cellular uptake by macrophages, foam cell formation and also causes the secretion of cytokines and growth factors from arterial wall cells. Non-enzymatic modifications of LDL (proteoglycans, glycosylation, immune complexes) and enzymatic modifications (lipases, oxygenases) were shown to affect the physicochemical (size, charge) as well as the biological (cellular uptake, secretion) properties of the lipoprotein. Of special interest is the oxidative modification of LDL which was demonstrated to occur in vivo. The mechanism of this process involves cellular lipid peroxidation and requires the binding of LDL to its receptor on macrophages. Some of the modifications can render the LDL more susceptible to other types of modifications (lipid modifications, aggregation, oxidation). As atherosclerosis is a multifactorial disease and since lipases and oxygenases exist in cells of the arterial wall, several forms of modified LDL may exist in vivo. These modifications can occur either in parallel or along different stages of atherogenesis. Inhibition of such LDL modifications may arrest the development of the atherosclerotic lesion.

Arteriosclerosis↗
PubMed1993

[Olive oil dietary supplementation decreases susceptibility of LDL to oxidation and its uptake by macrophages].

In atherogenesis, both peroxidation of low density lipoprotein (LDL) and accumulation of cholesterol in macrophages are involved. An oleic acid-rich diet was recently shown to reduce the susceptibility of rabbit and human LDL to in vitro oxidation. We therefore supplemented the diet of 10 normal men for 2 weeks with 50 g/d of olive oil, which is rich in oleic acid. This resulted in enrichment of their LDL with oleic acid (C18:1) and with sitosterol. After only 1 week LDL susceptibility to in vitro oxidation was significantly reduced, by 30% (p < 0.01). Macrophage uptake of LDL by the J-774A.1 macrophage-like cell line was reduced by 61%. We conclude that an olive oil-enriched diet possesses antiatherogenic properties, since it reduces the susceptibility of LDL to in vitro oxidation and inhibits uptake of LDL by macrophages.

Dietary Fats, Unsaturated↗
PubMed1993

Enhanced low-density lipoprotein degradation and cholesterol synthesis in monocyte-derived macrophages of patients with adult xanthogranulomatosis.

Adult xanthogranulomatosis is an uncommon disorder in which dermal macrophages accumulate cholesterol intracellularly despite normal plasma cholesterol levels. In an attempt to elucidate an underlying biochemical abnormality in this disorder, we studied the rates of 125I-labeled low-density lipoprotein degradation, and intracellular cholesterol synthesis, in human monocyte-derived macrophages of three patients with adult xanthogranulomatosis. In all three patients, the rates of cellular 125I-low-density lipoprotein degradation and of cholesterol synthesis were 22-37% and 14-84% higher than those of the respective normal controls (p < 0.01). These findings suggest that in MDM of adult xanthogranulomatosis patients, the uptake and degradation of low-density lipoprotein-derived cholesterol and intracellular cholesterol biosynthesis are enhanced. Because dermal macrophages are derived from blood monocytes, it is possible that such an enhancement might play a role in the accumulation of cholesteryl esters in the macrophages that form the xanthogranulomatosis lesions.

Adult↗
PubMed1993

Increased susceptibility to undergo lipid peroxidation of chylomicrons and low-density lipoprotein in celiac disease.

Gastrointestinal injury involves oxidative damage as the result of oxygen-derived free radicals which are formed during the inflammatory reactions. Chylomicrons which are synthesized by the intestine can thus be exposed to lipid peroxidation in celiac disease. Similarly, low-density lipoprotein (LDL) propensity to oxidation may be enhanced as a result of a direct or indirect effect of the oxidative process. To resolve these possibilities, plasma chylomicrons and LDL were isolated from a patient with celiac disease and from a control healthy subject before and 3 h after a fat-rich meal, and their propensity to copper-induced lipid peroxidation was then analyzed. The patient's chylomicrons, its LDL that was obtained before the fat-rich meal and its LDL that was obtained after the meal demonstrated 220, 39 and 48% elevation in their content of thiobarbituric-acid-reactive substances in comparison with the control lipoproteins. After a complete recovery of the patient's intestine, the susceptibility of the patient lipoproteins to in vitro oxidation returned toward normal levels. In the patient LDL fraction (obtained either before or after the fat-rich meal), but not in the patient's chylomicrons, the carotenoid content was reduced by 70%, vitamin E by 45%, and the LDL content of arachidonic acid was increased by 70% in comparison with the control lipoproteins. On recovery of the patient and return of the intestine to its normal morphology, normalization of all of these constituents was achieved.

Celiac Disease↗
PubMed1993

Dietary olive oil reduces low-density lipoprotein uptake by macrophages and decreases the susceptibility of the lipoprotein to undergo lipid peroxidation.

Low-density lipoprotein (LDL) oxidation and macrophage cholesterol accumulation are both involved in atherogenesis. Recently it was shown that feeding rabbits or humans with an oleic-acid-rich diet reduced the susceptibility of their LDL to in vitro oxidation. Since olive oil is highly enriched with oleic acid, we tested the effect of olive oil supplementation (50 g/day) to the diet of 10 healthy male subjects, during a 2-week period, on macrophage uptake of their LDL and on the propensity of their LDL to oxidation (with copper ions). Olive oil supplementation to the diet resulted in LDL enrichment with oleic acid (C18:1) and sitosterol. No effect on plasma cholesterol levels was found, but the LDL cholesteryl ester content was reduced (16%) whereas its unesterified cholesterol was increased (41%). Even after 1 week of the olive oil diet, the LDL susceptibility to in vitro oxidation was significantly reduced (p < 0.01). Macrophage uptake of LDL was studied by analysis of cellular cholesterol content and by analysis of the macrophage cholesterol esterification rates. LDL obtained after 1 and 2 weeks of the olive oil diet demonstrated reduced cellular uptake in comparison with LDL obtained before the supplementation of olive oil, by 50 and 61%, respectively. The LDL resistance to oxidation was shown by a reduction in its peroxide, malondialdehyde and conjugated diene content by 73, 28 and 32%, respectively. LDL incubation with oleic acid for the period of its oxidation with copper ions demonstrated a dose-dependent inhibition of lipoprotein oxidation by up to 72% as opposed to linoleic and arachidonic acids (50 microM) which increased LDL oxidation by 22 and 72%, respectively. Sitosterol, in a similar incubation system, inhibited LDL oxidation by up to 26%. We conclude that olive oil supplementation to the diet modifies LDL lipid composition and enriches the lipoprotein with oleic acid and sitosterol. The antiatherogenic properties of this modified lipoprotein may be related to its resistance to in vitro peroxidation and its reduced uptake by macrophages.

Adult↗
PubMed1993

Phospholipase D-modified low density lipoprotein is taken up by macrophages at increased rate. A possible role for phosphatidic acid.

Macrophage uptake of modified forms of LDL leads to cellular cholesterol accumulation. Upon incubation of LDL with phospholipase D (PLase D), a time- and enzyme dose-dependent production of phosphatidic acid (PA), paralleled by a rapid reduction in LDL phosphatidyl choline content (up to 65% within 15 min of incubation) was noted. No lipid peroxidation could be found in PLase D-modified LDL. Upon in vitro incubation of PLase D-LDL with copper ions, however, this modified LDL was substantially oxidized. The addition of 100 micrograms PA/ml to native LDL for the period of its in vitro oxidation resulted in a 63% elevation in the lipoprotein peroxides content. Incubation of PLase D-LDL with J-774A.1 macrophage-like cell line resulted in an increase in its cellular binding and degradation (up to 91 and 110%, respectively) in comparison with native LDL (via the LDL receptor). When PA was added to LDL before its incubation with the macrophages, a PA dose-dependent elevation in the cellular uptake of LDL (by up to twofold) was noted in comparison with LDL that was incubated without PA, suggesting that PA production in PLase D-LDL may be involved in the increased cellular uptake of PLase D-LDL. PLase D activity towards LDL was demonstrated in J-774A.1 macrophages. Human plasma was also shown to possess PLase D activity. Thus, PLase D modification of LDL may take place under certain pathological conditions and PLase D-LDL interaction with arterial wall macrophages can potentially lead to foam cell formation.

Animals↗
PubMed1993

Preferential inhibition of LDL oxidation by the all-trans isomer of beta-carotene in comparison with 9-cis beta-carotene.

The synthetic all-trans isomer of beta-carotene was recently shown to possess antioxidant properties towards the formation of oxidized low density lipoprotein. In the present study, the binding of the all-trans and the 9-cis isomers of beta-carotene to plasma lipoproteins was investigated, and the effect of these isomers on the susceptibility of plasma lipoprotein to lipid peroxidation and on macrophage uptake of oxidized LDL were studied. Both the synthetic all-trans isomer of beta-carotene and the natural beta-carotene from the algae Dunaliella Bardawil [which is composed of the all-trans (70%) and the 9-cis (30%) isomers], were found to bind similarly to all plasma lipoproteins, following the incubation of beta-carotene with purified lipoproteins or with whole plasma. Incubation of the beta-carotene isomers with whole plasma, followed by separation of the lipoproteins, revealed substantial carotene binding to very low density lipoprotein (VLDL) and to LDL and limited binding to high density lipoprotein (HDL). Lipid peroxidation of VLDL and LDL were significantly inhibited by beta-carotene. The synthetic beta-carotene, however, was twice as effective as the Dunaliella beta-carotene in inhibiting LDL lipid peroxidation (following LDL incubation with copper ions). Cellular degradation of oxidized lipoproteins (mediated via the scavenger receptor) was decreased by 40% and 18%, respectively, when they were prepared by incubation in the presence of synthetic or natural beta-carotene; the control oxidized LDL was prepared in the absence of beta-carotene.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Enhanced degradation of high density lipoprotein by peritoneal macrophages from nude mice is attenuated by interleukin-1.

Athymic nude mice are characterized by deficient cellular immunity due to almost complete absence of functional mature T-lymphocytes. Plasma HDL (the major cholesterol carrier in mice) cholesterol levels in nude mice were found to be reduced by 1.7 fold in comparison to control Balb/c mice. Cellular degradation of HDL by peritoneal macrophages (MPM) that were obtained from nude mice, was 2.5 fold greater in comparison to MPM obtained from Balb/c mice. Since nude mice lack cytokines that can affect lipid metabolism, intravenous administration of 10 micrograms/100g body weight of interleukin-1 (IL-1), tumor necrosis factor (TNF), or transforming growth factor (TGF) on HDL degradation by their PM, were investigated. IL-1 (but not TNF) reduced HDL (50 micrograms of protein/ml) cellular degradation from 810 +/- 34 to 350 +/- 12 ng/mg cell protein (p < 0.01) in nude mice. In control Balb/c mice, however, IL-1 as well as TNF enhanced macrophage degradation of HDL by 56% and 280%, respectively. TGF injection into nude mice (but not control mice) decreased HDL degradation by their MPM by 50%. We, thus, suggest that in nude mice the reduced plasma and HDL cholesterol levels are probably due to increased HDL degradation, which may be secondary to IL-1 and TGF deficiency.

Animals↗
PubMed1993

Intraperitoneal injection of platelet secretory products into mice increases macrophage uptake of oxidized low density lipoprotein.

Oxidized low density lipoprotein (LDL) (Ox-LDL) is taken up by macrophages at an enhanced rate and contributes to macrophage cholesterol accumulation and foam cell formation. Platelet secretory products have been shown to modulate the uptake of Ox-LDL by mouse peritoneal macrophages. This study is unique since mouse peritoneal macrophages were interacted with platelet conditioned medium (PCM, the supernatant that was obtained from collagen-treated washed human platelets) in the peritoneal cavity of the mice rather than in plastic dishes. Macrophages obtained from the peritoneal cavity of mice, 20 h after the injection of PCM (up to 30 micrograms of cholesterol/ml), demonstrated a substantial increment in the uptake of Ox-LDL. The effect of PCM demonstrated a dose- and time-dependent pattern. The cellular uptake of the lipoprotein, measured as the cellular Ox-LDL degradation and cholesterol esterification rates, was increased by up to 60% and 30% respectively in macrophages collected from PCM-injected mice in comparison to control mice. These effects were the result of PCM-induced increased affinity of Ox-LDL towards its receptor, and increased number of macrophage binding sites for Ox-LDL. Upon delipidation of PCM, only the protein fraction possessed the ability to increase the cellular uptake of Ox-LDL. Dialyzed PCM, which is deprived of low molecular weight substances, still expressed the stimulatory effect of PCM. Our results thus suggest that a protein-like factor that is secreted from activated platelets can increase in vivo the ability of macrophages to take up Ox-LDL, as was also previously shown in in vitro studies.

Animals↗
PubMed1992

Proteins derived from platelet alpha granules modulate the uptake of oxidized low density lipoprotein by macrophages.

Activated platelets secrete from their alpha granules a protein-like factor which stimulates the uptake of oxidized low-density lipoprotein (Ox-LDL) by macrophages. The aim of the present study was to evaluate the effect of three purified proteins obtained from platelet alpha granules: platelet-derived growth factor (PDGF), platelet factor-4 (PF-4), and beta-thromboglobulin (B-TG), on the uptake of Ox-LDL by macrophages. Cellular degradation of Ox-LDL by the J-774 A.1 macrophage-like cell line, that was preincubated for 18 h at 37 degrees C, with increasing concentrations of partially purified PDGF, (designated PDGF-CMS-III) was increased by up to 36% in comparison to control cells preincubated without PDGF. This effect was due to PDGF-mediated increase in the number of macrophage receptors for Ox-LDL. The enhanced uptake of Ox-LDL by PDGF resulted in an increase in cellular cholesterol content. Preincubation of macrophages with two types of recombinant PDGF dimers (10 ng/ml), revealed that PDGF-BB stimulated Ox-LDL cellular degradation by 64%, whereas PDGF-AB demonstrated only 34% stimulation, in comparison to control cells that were not treated with PDGF. The stimulatory effect of PDGF-CMS-III and PDGF-AB were reduced by 20% and 28%, respectively, when incubated in the presence of H-7, a specific protein kinase C inhibitor. When macrophages were preincubated with B-TG, cellular uptake of Ox-LDL was reduced by up to 30% at 100 ng B-TG/ml. This effect, however, was obtained only when B-TG was present in the incubation medium. Cellular degradation of Ox-LDL was not affected by preincubation of the cells with PF-4. Pretreatment of PCM with anti-PDGF or anti-B-TG antibodies abolished the effects of PCM on Ox-LDL degradation by macrophages. PDGF, thus, may represent the protein-like factor present in PCM which stimulates Ox-LDL degradation by macrophages, whereas B-TG may have a role in the recognition of PCM particles by the macrophage scavenger receptor. Modulation of macrophage cholesterol content by proteins secreted from activated platelets may have an important role in foam cell formation and atherosclerosis.

Antibodies↗