[Importance of early diagnosis of hyperlipidemias in the prevention of atherosclerosis].
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Arteriosclerosis↗
Biomedical subjects
M Aviram
Publications and source records attributed to M Aviram.
Angiotensin II stimulates macrophage-mediated oxidation of low density lipoproteins.
Increased incidence of myocardial infarction was found in hypertensive patients with high plasma renin activity and increased susceptibility to oxidation was demonstrated in low density lipoprotein (LDL) that was obtained from hypertensive patients. As lipid peroxidation was demonstrated in areas of the atherosclerotic lesion, we sought to analyze the effect of angiotensin II (AN-II) on LDL oxidation, both in vitro and in vivo. Preincubation of J-774 A.1 macrophage-like cell line or mouse peritoneal macrophages (MPM) with AN-II (10(-7) M) for 1 h at 37 degrees C, followed by the addition of LDL for a further 18 h of incubation, resulted in a substantial increase in macrophage-mediated oxidation of LDL (by 55% and 19%, respectively). Similarly, incubation of LDL with MPM harvested from AN-II-injected mice resulted in a substantially increased oxidation of the lipoprotein by up to 90% in comparison to saline-injected mice. Analysis of cellular lipid peroxidation in the MPM themselves, in both the in vitro and the in vivo studies, revealed a 25% or 90% increased macrophage lipid peroxidation, respectively. The mechanism of AN-II-mediated cellular lipid peroxidation involved AN-II binding to its receptor on macrophages as saralasin, an AN-II receptor antagonist, completely inhibited this effect. Inhibitors of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipases A2, C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation. Extracellular calcium ions, which active phospholipases, were also essential for AN-II-mediated macrophage lipid peroxidation since calcium channel blockers substantially inhibited cellular lipid peroxidation. Finally, the nature of the oxidant and oxygenase involved in AN-II-mediated cellular lipid peroxidation was studied using oxygenase inhibitors. Angiotensin II-mediated macrophage lipid peroxidation was found to involve the action of cellular NADPH oxidase as well as 15-lypoxygenase. We conclude that AN-II stimulates macrophage-mediated mediated oxidation of LDL secondary to cellular lipid peroxidation, and this may have a role in the accelerated atherosclerosis found in hypertensive patients.
Angiotensin II↗
Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation.
The effect of consumption of red or white wine (11% alcohol) with meals on the propensity of plasma and low-density lipoprotein (LDL) to undergo lipid peroxidation was studied in 17 healthy men who were divided into two groups: 8 received 400 mL red wine/d for 2 wk, and 9 received a similar amount of white wine. Red wine consumption for 2 wk resulted in a 20% reduction in the propensity of plasma to undergo lipid peroxidation (in the presence of a free-radical-generating system) as determined by the thiobarbituric acid reactive substances (TBARS) assay. In parallel, red wine consumption reduced the propensity of the volunteers' LDL to undergo lipid peroxidation (in response to copper ions) as determined by a 46%, 72%, and 54% decrease in the content of TBARS, lipid peroxides, and conjugated dienes in LDL, respectively, as well as by a substantial prolongation of the lag phase required for the initiation of LDL oxidation. On the contrary, dietary consumption of white wine for 2 wk resulted in a 34% increase in plasma's propensity to undergo lipid peroxidation and also in a 41% increased propensity of the LDL to undergo lipid peroxidation. The antioxidant effect of dietary red wine on plasma lipid peroxidation was not secondary to changes in the plasma vitamin E or beta-carotene content but could be related to the elevation of polyphenol concentration in plasma and LDL. Thus, some phenolic substances that exist in red wine, but not in white wine, are absorbed, bind to plasma LDL, and may be responsible for the antioxidant properties of red wine.
Adult↗
Macrophage uptake of oxidized LDL inhibits lysosomal sphingomyelinase, thus causing the accumulation of unesterified cholesterol-sphingomyelin-rich particles in the lysosomes. A possible role for 7-Ketocholesterol.
Macrophage uptake of oxidatively modified LDL (Ox-LDL), unlike the uptake of acetylated LDL (Ac-LDL), resulted in lysosomal accumulation of unesterified cholesterol (UC). As sphingomyelin (SM) binds UC with high affinity, we considered whether lysosomes also accumulate Ox-LDL-derived SM, and if such a phenomenon could be involved in the lysosomal trapping of Ox-LDL-derived UC. Incubation of J-774 A.1 macrophages with Ox-LDL increased the lysosomal accumulations of UC by 75% and SM by 63% compared with the effect of Ac-LDL. The addition of chlorpromazine, an inhibitor of lysosomal sphingomyelinase (SMase), to macrophages that were incubated with [3H]cholesteryl ester-labeled Ac-LDL also led to lysosomal accumulation of both SM and UC. 7-Ketocholesterol (7-KC), the major oxysterol in Ox-LDL, inhibited lysosomal SMase in a cell-free system. The addition of 7-KC to cells in the presence of [3H]choline- or [3H]cholesteryl ester-labeled Ac-LDL led to macrophage accumulation of SM or UC, respectively. Niemann-Pick type C disease (NP-C) is an inherited cholesterol-storage disease in which lysosomal SMase activity is attenuated after uptake of LDL. Incubation of monocyte-derived macrophages from two NP-C patients with Ac-LDL or Ox-LDL resulted in an accumulation of UC in the lysosomes, whereas normal monocyte-derived macrophages accumulate UC in their lysosomes after incubation with Ox-LDL but not Ac-LDL. These results suggest that inhibition of lysosomal SMase in NP-C cells or by 7-KC is required for lysosomal accumulation of UC. Analysis of the macrophage lysosomal extract (following cell incubation with Ox-LDL) by density-gradient ultracentrifugation and gel-filtration chromatography revealed the presence of a particle consisting of UC, SM, 7-KC, and apoB-100. We conclude that 7-KC in Ox-LDL can inhibit lysosomal SMase, thus leading to the accumulation of SM, which binds UC avidly and inhibits its further cellular processing out of the lysosome. As UC-SM particles of lysosomal origin exist in the atherosclerotic lesion, the formation of such particles may result from an impaired processing of Ox-LDL by arterial wall macrophages during early atherogenesis.
Animals↗
HDL apolipoprotein A-I attenuates oxidative modification of low density lipoprotein: studies in transgenic mice.
Epidemiological evidence suggests that plasma high-density lipoprotein (HDL) is protective against coronary artery disease, whereas oxidatively modified low density lipoprotein is atherogenic. Human apolipoprotein A-I transgenic mice with overexpression of the human apolipoprotein A-I gene have increased plasma levels of apolipoprotein A-I and HDL-cholesterol. We analyzed LDL oxidation by determination of LDL associated malondialdehyde, peroxides and conjugated dienes. The present study demonstrates that HDL from both normal and human apolipoprotein A-I transgenic mice at similar concentrations inhibits LDL (protein concentration 500 mg/l) lipid peroxidation, but the effect of the human apolipoprotein A-I transgenic mice HDL was two-fold greater than that of HDL derived from normal mice. In addition, the electrophoretic mobility of oxidatively modified LDL was reduced about two-fold in the presence of human apolipoprotein A-I transgenic mice HDL than that obtained in the presence of normal mice HDL. We thus suggest that human apolipoprotein A-I possesses antioxidant properties which might neutralize LDL lipid peroxidation. This may underline the mechanism responsible for the lower prevalence of atherosclerosis in subjects with high plasma levels of HDL and apolipoprotein A-I.
Animals↗
Cyclic AMP-related and cation-affected human platelet chloride transport regulation.
Cystic fibrosis has been characterized as a defect in the regulation of cyclic AMP-dependent transepithelial chloride transport. The activation of cyclic AMP-dependent protein kinase A by cyclic AMP occurs normally in cystic fibrosis cells, but they fail to transport chloride ions in response to protein kinase A stimulation. Defective chloride secretion and abnormal electrolyte transport occurs in several organs including the lung, sweat glands, intestine and pancreas. The present work was aimed at exploring whether the same or similar regulatory systems are functional in platelets, and if they are altered or deficient in individuals with cystic fibrosis. Chloride transport in platelets from normal subjects and from cystic fibrosis patients was measured by cell sizing techniques where chloride permeability is the limiting factor. In platelets from healthy volunteers, the chloride channel blocker, 5-nitro-2-(3-phenylpropylamino) benzoic acid, inhibits the transport in a dose-dependent manner. The preservation of chloride transport capability is shown to be dependent upon the presence of either Ca2+ or two divalent cation substitutes, Cd2+ or Cu2+. It is also shown that in normal subjects 0.1 mumol/l prostaglandin E1, which elevates cyclic AMP 6 times and abolishes platelet aggregation, significantly enhances the rate constant of the transport. Furthermore, in five out of nine cystic fibrosis patients studied, platelet chloride transport did not respond to stimulation by prostaglandin E1.
Adolescent↗
Fatal multiple organ failure following massive hornet stings.
We describe a fatal outcome in a three-year-old child following massive stings by the oriental hornet (Vespa orientalis). The primary clinical features were coma, respiratory failure, coagulopathy, renal failure and liver dysfunction. On postmortem the main organs involved were brain, lungs, kidney and liver.
Animals↗
Protective effect of low concentrations of oxidized low-density lipoprotein on endothelial cell integrity.
BACKGROUND: Increasing evidence suggests that oxidized low-density lipoprotein (LDL) is associated with the development of atherosclerosis in vivo. Because endothelial injury contributes to the development of the atherogenic , we investigated the efficacy of oxidized LDL on the integrity of human umbilical cord endothelial cells (HUVECs) by analyzing cytotoxicity and cell detachment. METHODS: The cellular integrity of cultured endothelial cells labeled with chromium-51. RESULTS: Low concentrations of oxidized LDL (25-50 micrograms protein/ml) induced morphological changes (cell elongation and formation of gaps in the cobblestone monolayer), decreased cellular cytotoxicity (by 13% compared with control). At higher concentrations of oxidized LDL (100 micrograms protein/ml), however, increases in cytotoxicity (by up to 70%) and cellular detachment (by up to 90%) were demonstrated. Native LDL, which was not oxidized in out cell system, did not induce any changes either in cytotoxicity or in cell detachment. The protective effect of low oxidized LDL concentrations against endothelial cell cytotoxicity and detachment was abolished by indomethacin (microM), indicating the involvement or prostaglandin synthesis in this protection. CONCLUSION: Our experiments suggest that oxidized LDL-induced alterations of endothelial cells involve a sequence of events leading from a non-cytotoxic protective stage to endothelial perturbation.
Cell Adhesion↗
Low density lipoprotein-cholesteryl ester-derived linoleic acid is mainly incorporated into the phospholipid component of the macrophages.
The cellular metabolism of the cholesterol in the low density lipoprotein cholesteryl ester (LDL-CE) moiety is well characterized, whereas the cellular fate of the fatty acid (mainly linoleic acid) in the LDL-CE has not been studied in detail. The distribution of the LDL-CE-derived linoleic acid among cellular lipids was studied in J-774 A.1 macrophages, using LDL that was radiolabeled in the linoleic acid of its CE moiety. Macrophages were incubated with radiolabeled LDL for 4 h at 4 degrees C, washed and further incubated for up to 24 h at 37 degrees C in a fresh medium (without LDL). The distribution of the linoleic acid among cellular lipids was then analyzed. After 20 min of incubation, most of the linoleic acid was found in the CE fraction as a constituent of the internalized LDL, and the CE-associated linoleate was progressively decreased. In parallel, the linoleic acid was found to be esterified into the macrophage phospholipids (mostly in the macrophage phosphatidyl choline fraction), accounting for up to 62% of the total cellular labeled linoleic acid after 24 h of incubation. We conclude that the fatty acid derived from the hydrolysis of the LDL-CE moiety in macrophages is mainly incorporated into the cellular phospholipids where it can serve for various cellular metabolic processes.
Animals↗
Reduced cellular cholesterol content in peroxisome-deficient fibroblasts is associated with impaired uptake of the patient's low density lipoprotein and with reduced cholesterol synthesis.
Mammalian cells acquire cellular cholesterol by de novo synthesis as well as by uptake of low density lipoprotein (LDL). Peroxisomes contain enzymes involved in the synthesis of cholesterol, and peroxisome-deficient (PD) patients have been shown to have hypocholesterolemia and abnormal LDL. We therefore decided to study whether cholesterol synthesis and cellular uptake of LDL are impaired in cultured PD fibroblasts. The present study demonstrates a significantly lower cellular cholesterol mass in fibroblasts from three PD patients, as compared to control cells (41-59% of controls). The rate of cholesterol synthesis was also reduced in all three PD cell lines, being 16-20% of the control values. LDL binding and degradation by fibroblasts were 3- to 5-fold higher in the PD cells as compared to control cells. Similarly, enrichment of normal fibroblasts with tetracosanoic acid (C-24:0), a situation that could mimic the in vivo accumulation of very long chain fatty acid (VLCFA) in PD cells, caused LDL binding and degradation to be 4-fold higher than in non-treated cells. On the other hand, the uptake of LDL derived from PD patients by normal fibroblasts was markedly reduced (by up to 67%) in comparison to the cellular uptake of normal LDL. Similar results were obtained in PD cells. This study demonstrates a lower cellular cholesterol content and reduced cholesterol synthesis rate in PD cell lines. In addition, we demonstrate that regulation of the uptake of normal LDL by cellular LDL receptors is operative in PD cells, whereas LDL derived from PD patients is not recognized normally by the LDL receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Cholesterol↗
Oxidative modification of low density lipoprotein and its relation to atherosclerosis.
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Arteriosclerosis↗
LDL-platelet interaction under oxidative stress induces macrophage foam cell formation.
The atherosclerotic lesion consists of macrophages filled with cholesterol derived from oxidized-low density lipoprotein (Ox-LDL) and also contains platelet aggregates. Under oxidative stress on platelet activation, and enhanced macrophage uptake of Ox-LDL (secondary to platelet-mediated modification of the lipoprotein or to the interaction between Ox-LDL and arterial wall macrophages). The following data demonstrate that all of these mechanisms are operable in vitro: 1) upon platelet incubation with Ox-LDL, platelet aggregation and release are substantially increased; 2) under oxidative stress (in the presence of ferrous ions) platelets' phospholipids are oxidized, paralleled by increased platelets activation; 3) platelet conditioned medium (PCM) from collagen activated platelets, can modify LDL to a form which is taken up by macrophages at enhanced rate; 4) under oxidative stress (in the presence of copper ions) platelets can oxidatively modify native LDL; 5) PCM increases macrophage uptake of Ox-LDL, secondary to the stimulatory effect of PDGF (which is present in PCM) on the macrophage receptors for Ox-LDL. In conclusion, we suggest that the involvement of platelets in macrophage foam cell formation is related to platelet released factors which can either oxidize the LDL or increase the uptake of Ox-LDL by the macrophages. These effects of platelets on Ox-LDL, as well as the activation of blood platelets by Ox-LDL, contribute to the formation of the atherosclerotic lesion.
Animals↗
Role of HDL apolipoprotein E in cellular cholesterol efflux: studies in apo E knockout transgenic mice.
The role of apo E in aspects of reverse cholesterol transport was studied in apolipoprotein E-deficient mice. These animals develop rampant atherosclerosis. The efflux of cholesterol from mouse peritoneal macrophages (MPM) was 40% lower when induced by high density lipoprotein (HDL) from apo E-deficient mice, compared to the effect of HDL from normal mice. On adding apo E to apo E-deficient HDL, cholesterol efflux from the macrophages increased by 35%, approaching the degree of efflux obtained with normal HDL. This HDL (normal or apo E-deficient)-induced cholesterol efflux was similar in peritoneal macrophages derived from both normal and apo E-deficient mice, suggesting that the HDL apo E rather than the macrophage apo E is responsible for the stimulation of cellular cholesterol efflux. On determining cholesterol efflux specifically from the macrophage plasma membrane, the level of efflux was similar for both HDL preparations, suggesting that apo E in HDL is important for cholesterol translocation to the plasma membrane, the initial step in reverse cholesterol transport. It is concluded that the enhanced atherosclerosis in apo E-deficient mice could be related, at least partly, to the impaired efflux of LDL derived cholesterol from macrophages of the arterial wall.
Animals↗
[Plasma lipid peroxidation: inhibited by drinking red wine but stimulated by white wine].
The effects of drinking red or white wine (11% alcohol) on the propensity of plasma and low density lipoprotein (LDL) to undergo lipid peroxidation (LP) was studied. 8 healthy men drank 400 ml of red wine a day for 2 weeks and 9 drank white wine similarly. The red wine supplementation resulted in a 20% similarly. The red wine supplementation resulted in a 20% reduction in the propensity of their plasma to undergo LP (in the presence of a free radical-generating system) and a 46% reduction in that of their LDL to undergo LP (in response to copper ions). Contrarily, drinking white wine for 2 weeks resulted in a 33% increase in propensity of plasma to undergo LP and in a 57% increase in that of LDL to undergo LP. The antioxidant effect of drinking red wine on plasma LP can be related to increase in plasma high density lipoprotein concentration, as well as to increase in plasma and LDL polyphenols. We conclude that some phenolic substance present in red, but not in white wine, may be responsible for the antioxidative properties of red wine supplementation for LDL LP, and thus may possess antiatherogenic properties.
Alcohol Drinking↗
Increased plasma and lipoprotein lipid peroxidation in apo E-deficient mice.
Apo E-deficient mice which are highly atherogenic animals were used in order to study their plasma and lipoprotein lipid peroxidation in the absence or presence of oxidative stress. We have demonstrated that plasma from apo E knockout mice demonstrated increased lipid peroxidation both in the absence and in the presence of a free radical generating substance, 2,2-Azobis-(2-amidinopropane) hydrochloride (AAPH). Similarly, low and very low-density lipoprotein (LDL and VLDL) from apo E-deficient mice, but not their high-density lipoprotein (HDL), demonstrated increased lipid peroxidation. We suggest that in apo E-deficient mice, accelerated atherosclerosis is associated with increased lipid peroxidation of plasma, LDL and VLDL, as well as increased susceptibility of these lipoproteins to undergo lipid peroxidation under oxidative stress.
Animals↗
Low density lipoprotein isolated from patients with essential hypertension exhibits increased propensity for oxidation and enhanced uptake by macrophages: a possible role for angiotensin II.
In patients with essential hypertension, the increased risk for atherosclerosis is related not only to the blood pressure levels per se, but also to other, unknown, factors. Recent observations have indicated that oxidation of low density lipoprotein (LDL) and macrophage uptake of oxidized LDL are implicated in human atherosclerosis. We tested both the susceptibility of LDL, derived from hypertensive patients, to lipid peroxidation as well as its uptake by macrophages, in comparison with control LDL obtained from healthy subjects. The LDL that was derived from 25 patients with essential hypertension demonstrated increased propensity for lipid peroxidation with a 63%, 91% and 69% elevation in the content of the lipoprotein malondialdehyde, peroxides and conjugated dienes, respectively, in comparison with control LDL. Minimally modified LDL (MM-LDL) (prepared by 6 months' storage of the LDL at 4 degrees C) derived from the hypertensive patients also demonstrated increased lipid peroxidation with a 94%, 130% and 96% elevation in lipoprotein malondialdehyde, peroxides and conjugated dienes, respectively, compared with the control LDL. The susceptibility of the patients' LDL to lipid peroxidation decreased by 32% and 44% (measured as malondialdehyde) after 3 weeks of therapy with the angiotensin converting enzyme inhibitors captopril and enalapril, respectively, with no parallel reduction in the patients' blood pressure. The patients' LDL was shown to contain increased content of lipid peroxides and unsaturated fatty acids, which may explain its increased susceptibility to lipid peroxidation. In vitro experiments revealed that LDL can bind angiotensin II, and that angiotensin II has a stimulatory effect on copper-mediated oxidation of LDL, as well as on LDL degradation by macrophages. These results were secondary to cell-mediated oxidation of the LDL and to its cellular uptake via the scavenger receptor. We conclude that LDL derived from patients with essential hypertension is more susceptible to lipid peroxidation than control LDL, and this may be secondary to angiotensin II stimulation of LDL lipid peroxidation in these patients. Furthermore, this LDL demonstrates enhanced cellular uptake by macrophages in comparison with normal LDL which can also be related to angiotensin II-mediated LDL oxidation. Both these phenomena have been shown to be associated with accelerated atherosclerosis, and thus suggest a new mechanism for increased atherogenecity in hypertensive patients.
Adult↗
Iron induces lipid peroxidation in cultured macrophages, increases their ability to oxidatively modify LDL, and affects their secretory properties.
The present study demonstrates for the first time that iron ions can induce lipid peroxidation in intact macrophages without causing cell death. Macrophage lipid peroxidation increases cell-mediated oxidation of LDL, enhances the release of interleukin 1 and inhibits the release of apolipoprotein E from the macrophages. When cultured macrophages were exposed to ferrous ions (50 microM FeSO4) for 4 h at 37 degrees C, cellular lipid peroxidation (measured by analyses of malondialdehyde (MDA), conjugated dienes (CD), and lipid peroxides (PD)) increased 2-4-fold in comparison with non-treated cells. This process was iron-dose dependent, reached its maximum after 4 h of incubation, and was accompanied by 68% and 53% reductions in the content of the cellular linoleic (18:2), and arachidonic acid (20:4), respectively, and by 29% and 36% reductions of cellular vitamin E and vitamin A, respectively. Cell viability (measured by trypan blue exclusion, by [3H]thymidine incorporation into DNA, by analysis of the release of lactate dehydrogenase (LDH) or [3H]adenine), and cell morphology (studied by scanning electron microscopy) were not significantly affected by the iron-induced oxidative stress. Manitol and dimethylthiourea (DMTU), but not catalase or superoxide dismutase (SOD), significantly inhibited iron-induced cellular lipid peroxide formation, suggesting that hydroxyl radical, but not superoxides or hydrogen peroxides, mediated the iron-induced cellular lipid peroxidation. Incubation of LDL (0.2 mg of protein/ml) with oxidized macrophages resulted in LDL lipids peroxidation, as evidenced by an 8-fold increase in the LDL associated MDA in comparison with LDL that was incubated under similar conditions with non-oxidized macrophages. Furthermore, oxidation of LDL by oxidized macrophages in the presence of copper ions (10 microM CuSO4) was 2-fold higher in comparison with oxidation of LDL by non-oxidized macrophages. The release of apolipoprotein E from oxidized macrophages decreased by 50%, whereas macrophage release of beta-glucuronidase and of interleukin-1 beta increased by 83% and by a factor of 6, respectively. This study demonstrates for the first time that iron ions induce oxidation of the cellular polyunsaturated fatty acids in intact macrophages and that this cellular lipid peroxidation can subsequently induce LDL oxidation.
Animals↗
Lovastatin decreases plasma and platelet cholesterol levels and normalizes elevated platelet fluidity and aggregation in hypercholesterolemic patients.
The lipid composition of whole platelets and the fluidity of platelet membranes, as well as the sensitivity of the cell to aggregation, were studied in type IIA hypercholesterolemic human subjects before and after treatment with lovastatin. Fourteen patients with primary hypercholesterolemia having initial cholesterol levels of 383 +/- 52 mg/dL (mean +/- standard deviation) were studied and compared with 21 control subjects having cholesterol levels of 187 +/- 32 mg/dL. Lovastatin was administered orally at a starting dose of 40 mg daily. The dose was increased to 80 mg daily for eight patients who did not achieve the target cholesterol level of 200 mg/dL at 6 weeks. Serum cholesterol level was decreased by 37% following 20 weeks' administration of the drug. The fluidity of platelet membranes expressed in terms of the fluorescence anisotropy parameter was determined using the probe 1,6-diphenyl-1,3,5-hexatriene (DPH). When compared with platelets obtained from normocholesterolemic controls, platelets from hypercholesterolemic patients had a higher molar ratio of cholesterol to phospholipids ([C/PL] 0.86 +/- 0.15 v 0.57 +/- 0.06 for controls) and of phosphatidylcholine to sphingomyelin ([PC/SM] 2.64 +/- 0.87 v 2.00 +/- 0.15 for controls), enhanced fluidity (anisotropy parameter at 37 degrees C of 0.892 +/- 0.066 v 0.977 +/- 0.065 for controls), and a greater tendency to aggregate (aggregation of 84.2% +/- 6.3% v 78.5% +/- 7.6% for controls).(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗