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D Harats

Publications and source records attributed to D Harats.

At least 73 records · Page 4Linked to original sources
PubMed1998

Induction of early atherosclerosis in LDL-receptor-deficient mice immunized with beta2-glycoprotein I.

BACKGROUND: Immunization with beta2-glycoprotein I (beta2GPI), the probable target of autoimmune anticardiolipin antibodies, results in experimental antiphospholipid syndrome in different mouse strains. The present study was undertaken to evaluate the effect of beta2GPI immunization on the progression of atherosclerosis. METHODS AND RESULTS: In the first experiment, 3 groups of LDL receptor-deficient (LDL-RD) mice (n=15 per group) were immunized with either beta2GPI or ovalbumin or were not immunized and were fed a chow diet for 12 weeks. In a second experiment, 3 groups of LDL-RD mice (n=10 per group) were immunized similarly and fed an atherogenic diet for 6 weeks. All beta2GPI-immunized mice developed high titers of anti-beta2GPI antibodies as well as a specific lymph node proliferation to beta2GPI. The average cholesterol levels did not differ between the mice fed similar diets, regardless of the immunization protocol. Atherosclerosis was enhanced in the beta2GPI-immunized mice (mean aortic lesion, 26 000+/-5700 microm2) in comparison with their ovalbumin-immunized (mean, 3000+/-1099 microm2; P<0.01) and nonimmunized (mean, 2250+/-700 microm2; P<0.01) littermates. The average lesion size in the beta2GPI-immunized mice fed an atherogenic diet (mean, 98 000+/-8305 microm2) was larger than the ovalbumin-immunized mice (mean, 81 250+/-12 933 microm2; P=NS) or the nonimmunized controls (mean, 75 625+/-7281 microm2; P=NS). The atherosclerotic plaques in the beta2GPI-immunized mice appeared to be more mature, and denser infiltration of CD4 lymphocytes was present in the subendothelium of the aortic sinuses from this group of mice. CONCLUSIONS: The results of the present study provide the first direct evidence for the proatherogenic effect of ss2GPI immunization and establish a new model for immune-mediated atherosclerosis.

Animals↗
PubMed1998

Hyperimmunization of apo-E-deficient mice with homologous malondialdehyde low-density lipoprotein suppresses early atherogenesis.

The role of the immune system in modulating atherosclerosis has recently been the subject of intensive research. Several previous authors have put forward a paradigm of the autoimmune process occurring in the vicinity of the plaque. Two recent studies have shown that immunization of rabbits with homologous modified low-density lipoprotein (LDL) led to suppression of atherosclerosis. In the current study we evaluated the effects of homologous malondialdehyde (MDA)-LDL immunizations on atherogenesis in apo-E-deficient mice. Two groups of female chow-diet-fed, apo-E-deficient mice (n = 10) were either immunized with homologous MDA-LDL or with phosphate buffer saline (PBS) at 2-week intervals. The mice were sacrificed 12 weeks following the primary immunization. The MDA-LDL-immunized mice were shown to develop high titers of anti-MDA-LDL antibodies. Atherosclerosis, determined by the lesion size at the aortic sinus, was significantly suppressed in the MDA-LDL-immunized mice as compared with their littermates immunized with PBS (mean area +/- S.D.; 74000 +/- 17300 microm2 versus 158000 +/- 12800 microm2; P < 0.01). No differences were found between the groups with respect to the cellular composition of the atherosclerotic plaques. The results of this study show that immunization with MDA-LDL has a protective effect in apo-E-deficient mice, and further suggests that this mouse model is suitable for studies of immunomodulation.

Animals↗
PubMed1998

Citrus fruit supplementation reduces lipoprotein oxidation in young men ingesting a diet high in saturated fat: presumptive evidence for an interaction between vitamins C and E in vivo.

To determine the effects of vitamin C on cardiovascular risk factors, we studied dietary vitamin C enrichment in 36 healthy male students consuming a diet high in saturated fatty acids. After a 1-mo run-in period during which the subjects consumed approximately 50 mg ascorbic acid/d (low-C diet), half of the subjects were randomly assigned to receive 500 mg ascorbic acid/d for an additional 2 mo (high-C diet). Plasma ascorbic acid increased from 13.5 micromol/L with the low-C diet to 51.7 micromol/L with the high-C diet. Plasma cholesterol increased slightly with the high-C diet, but not above baseline concentrations. This increase was offset by an increase in the lag period of in vitro LDL oxidation, which correlated with plasma ascorbic acid concentrations (r = 0.735, P = 0.0012). Lipoprotein vitamin E concentrations were unchanged with the two diets. There were no effects on concentrations of fibrinogen or factor VII. The fact that ascorbic acid reduced the in vitro susceptibility of lipoproteins to oxidation provides presumptive evidence for an interaction between aqueous and lipophilic antioxidants (vitamins C and E ) in maintaining the integrity of LDL particles.

Adult↗
PubMed1998

Atherosclerosis and the antiphospholipid syndrome: a link unravelled?

Atherosclerosis is a multifactorial disease that involves the arterial system. Recent data suggest that immune and autoimmune factors play a dominant role in mediating the progression of atherosclerosis. Among these factors, humoral response to modified forms of LDL and heat-shock proteins has been shown to be influential. The antiphospholipid syndrome (APS) entails clinical manifestations that result from a hypercoagulable state. Antibodies to phospholipids and to beta2-glycoprotein I have been suggested to confer the tendency to thrombosis. In a set of recent studies, we have been able to show that generation of antiphospholipid antibodies in mice is associated with enhanced atherosclerosis. These findings imply that APS and atherosclerosis may share a common etiologic background, which may have direct implications for the management of both conditions.

Animals↗
PubMed1997

Atherosclerosis in LDL-receptor knockout mice is accelerated by immunization with anticardiolipin antibodies.

Atherosclerosis is a process initiated by accumulation of macrophages in distinct areas of endothelial cell damage and uptake of large amounts of lipids. Recently, it has been shown that the immune system plays an active part in the progression of the atherosclerotic plaque although its precise role has not yet been elucidated. Anticardiolipin antibodies (aCL) are generally found in the sera of patients with the antiphospholipid syndrome (APS) and are associated with a prothrombotic state. Several authors have demonstrated that aCL can activate platelets and endothelial cells as well as increase oxidized low density lipoprotein (LDL) uptake by macrophages. In the present study we sought to assess the effect of immunization with aCL (Ab1, leading to the production of mouse aCL-Ab3) on the progression of atherosclerosis. Two groups of 8-weeks old female LDL-receptor knockout mice (n = 13 per group) were immunized with IgG purified from the serum of an APS patient or with normal human IgG, respectively. The aCL immunized mice developed high titres of 'self' aCL (detected using the standard aCL ELISA) as compared with the normal human IgG immunized mice, whereas no differences were noted between both study groups with respect to the serum lipid levels. The extent of fatty streak formation was significantly higher in the aCL immunized mice in comparison with the human IgG injected mice (mean aortic lesion size of 5308 +/- 471 microns2 vs 1027 +/- 184 microns2, respectively, P < 0.01). The immunohistochemical analysis of the atherosclerotic plaques from both mouse groups did not display differences in cellular composition. The results of the study show that mouse aCL induced by immunization with human aCL from an APS patient enhance atherogenesis in LDL-RKO mice and imply that these antibodies may play a role in atherosclerosis development in patients with the APS.

Animals↗
PubMed1996

Emerging cross-regulatory roles of immunity and autoimmunity in atherosclerosis.

Atherosclerosis is a histopathological process of a multifactorial origin. Whereas the genetic and biochemical causes received considerable attention, the involvement of the immune system has generally been considered negligible. In recent years evidence has been presented to support the dominant role played by the immune system in atherosclerosis. Two major antigenic determinants against which the immune response may be triggered have been suggested, namely the heat shock protein 60/65 and oxidized low density lipoprotein. The current paper reviews the data regarding the involvement of the immune system in atherogenesis with respect to the antigenic candidates mentioned above.

Arteriosclerosis↗
PubMed1995

Targeting gene expression to the vascular wall in transgenic mice using the murine preproendothelin-1 promoter.

To develop a system for overexpressing genes in the vascular wall, we created transgenic mice using the reporter gene luciferase and the murine preproendothelin-1 promoter. In vitro analysis suggested that the murine 5'-flanking region contained endothelial-specific elements in a 5.9-kb fragment. Five transgenic mice colonies established from independent founders all exhibited the highest level of luciferase activity in the aorta with up to 8,540 light units per microgram of protein. Immunohistochemistry with anti-luciferase antisera revealed high levels of expression in the endothelial cells of both large and small arteries and lower levels of expression in veins and capillaries. Significant expression was also seen in arterial smooth muscle cells and in select epithelial surfaces which is consistent with the known distribution of endothelin-1 in mammals. The further demonstrate the targeting capability of this system, we overexpressed the lipid-peroxidating enzyme, human 15-lipoxygenase, in the vessel wall of transgenic mice. As with luciferase, expression of active enzyme and immunohistochemical localization in vascular cells were documented in transgenic animals. Hence, this new system can be used to direct expression of molecules to the vascular wall for the purpose of examining the biological significance of either overexpression or inhibition of select proteins.

Animals↗
PubMed1993

Efficacy and safety of pravastatin once daily in primary moderate hypercholesterolemia: the Israeli experience.

Seventy-seven hypercholesterolemic patients participated in a 26-week, multicenter, randomized, double-blind, placebo-controlled study that investigated the efficacy and safety of pravastatin therapy. All patients had primary moderate hypercholesterolemia (total cholesterol 200-300 mg/dl, at the end of a 6-week dietary run-in period) and two additional coronary risk factors. Pravastatin, 20-40 mg/day given at bedtime, reduced total cholesterol by 19-22%, LDL-cholesterol by 24-30%, triglycerides by 10-30% and increased HDL-cholesterol by 9-13%. The drug caused mild elevation in alanine aminotransferase and aspartate aminotransferase. Almost all these elevations were within normal limits and no patient was clinically symptomatic. No other significant differences were observed between the pravastatin and the placebo-treated groups with regard to other adverse effects and to patient compliance and withdrawal. It is concluded that pravastatin has a beneficial effect on the lipid profile and that the drug is safe and well tolerated.

Adult↗
PubMed1992

Effects of diets rich in monounsaturated fatty acids on plasma lipoproteins--the Jerusalem Nutrition Study. II. Monounsaturated fatty acids vs carbohydrates.

Seventeen male Yeshiva students were randomly allocated to a crossover study with two 12-wk dietary periods of monounsaturated fatty acids (MUFAs) vs a carbohydrate (CHO)-rich diet while concentrations of saturated (SFAs) and polyunsaturated (PUFAs) fatty acids were kept similar. Total plasma cholesterol (TC) decreased significantly by approximately 7.7% and low-density-lipoprotein cholesterol (LDL-C) by 14.4% on the MUFA diet, whereas on the CHO diet no significant change in cholesterol concentrations occurred, in contrast to that predicted by the equations of Keys and Hegsted. Concentrations of high-density-lipoprotein cholesterol (HDL-C) did not change significantly on either diet. On the MUFA diet there was a significantly lower proneness to peroxidation of plasma and LDL lipids and less extensive metabolism of conditioned LDL by peritoneal macrophages. We conclude that dietary MUFAs lower TC and LDL-C concentrations, independently of other dietary fatty acids and in addition may reduce the susceptibility of LDL to oxidative stress.

Adult↗
PubMed1991

Fish oil ingestion in smokers and nonsmokers enhances peroxidation of plasma lipoproteins.

The effect of fish oil ingestion (10 g MaxEPA/day) on the susceptibility of plasma lipoproteins to peroxidation was examined in 20 smokers (study A and B) and 22 nonsmokers (study C). The subjects were examined at the onset of each study (baseline values), divided into control and experimental groups and reexamined 4 weeks later. Smokers were examined 40 h after abstention from smoking (0 time) and 90 min after acute smoking (4-6 cigarettes). The parameters studied were TBARS, which provide an indication of peroxidative injury, and metabolism of conditioned LDL by macrophages as a biological indicator. These parameters were significantly higher (P less than 0.05-0.001) when the 90 min values of smokers were compared to time 0. After 4 weeks of fish oil ingestion, a significant rise above baseline values (33-50%) in plasma and LDL TBARS was found in smokers examined at time 0 and after acute smoking. Peroxidative modification of LDL isolated from smokers fed fish oil resulted in significantly higher TBARS (34-41%) and its metabolism by macrophages was higher (65-139%) compared to baseline values. In nonsmokers, the baseline values of the above parameters were lower than in smokers. Ingestion of fish oil resulted in a significant rise in TBARS in plasma (33%), LDL (137%), conditioned LDL (36-40%) and metabolism of conditioned LDL (70%) by macrophages. In 6 nonsmokers and 4 smokers, 400 mg of vitamin E/day were given with the fish oil. In the nonsmokers, vitamin E counteracted the effect of fish oil more effectively than in the smokers. In the light of the present results, indiscriminate recommendation of fish oil supplementation to the population at large should be cautioned.

Animals↗
PubMed1990

Effect of vitamin C and E supplementation on susceptibility of plasma lipoproteins to peroxidation induced by acute smoking.

The effect of acute smoking on plasma lipoproteins was studied in seventeen smokers. In study 1, 7 subjects were examined prior to and 2 weeks after supplementation with vitamin C. In study 2, the effect of acute smoking was first determined in 10 additional subjects and subsequently they were divided into 3 groups, 3 and 4 subjects were supplemented with vitamin C or E, respectively, for 4 weeks, and 3 remained untreated. Plasma and LDL TBARS were examined at time zero (i.e., 40-48 h after total abstention from smoking) and at 90 min after acute smoking (5-7 cigarettes). In all 17 subjects examined prior to vitamin supplementation, significantly higher TBARS values were found in plasma, native LDL and LDL conditioned with smooth muscle cells (SMC) when the 90 min values were compared to 0 time. The LDL isolated after 90 min and conditioned with SMC was metabolized more extensively by mouse peritoneal macrophages than its zero time counterpart. The differences between the 0 time and 90 min values were not seen after the subjects had been supplemented with vitamin C for 2 or 4 weeks or with vitamin E for 4 weeks. The present results indicate that acute smoking exerts an oxidative stress on plasma lipoproteins and that higher plasma levels of natural antioxidants, such as vitamins C and E have a protective role.

Adult↗
PubMed1989

Prolonged reversible acute renal failure in focal glomerulonephritis with severe nephrotic syndrome in an elderly patient.

A clinical report of a 67-year-old woman who developed reversible acute renal failure due to focal glomerulonephritis with severe nephrotic syndrome is presented. The patient required four weeks' dialysis treatment but recovered completely. The role of temporary dialysis and diuretics on the clinical course and the reversibility of the process in old age is discussed.

Acute Kidney Injury↗
PubMed1989

Cigarette smoking renders LDL susceptible to peroxidative modification and enhanced metabolism by macrophages.

The effect of cigarette smoking on peroxidation of plasma low density lipoprotein (LDL) was studied in 16 smokers aged 23-56 years; 12 nonsmokers of similar age served as controls. The smokers were asked to refrain from smoking 24-40 h prior to testing. Peroxidation was assessed by determination of thiobarbituric acid reactive substances (TBARS) in fresh plasma and LDL and by an increase in 125I-LDL metabolism by peritoneal macrophages. There was no difference in TBARS in freshly prepared plasma or LDL of smokers and nonsmokers. However, LDL of smokers, conditioned by incubation with bovine aortic smooth muscle cells (SMC), had 2-fold or higher TBARS values when compared to SMC conditioned LDL of nonsmokers. 2-4-fold higher TBARS values were seen also in SMC conditioned LDL when the comparison was made between LDL isolated from plasma before smoking of 6-7 cigarettes (time 0), and LDL of the same individual isolated from plasma 90 min thereafter. The metabolism of SMC conditioned 125I-LDL by peritoneal macrophages was examined; LDL isolated from plasma of smokers at time 0 was metabolized twice as avidly as LDL of nonsmokers and a further increase was seen with LDL isolated 90 min after acute smoking. The present results indicate that cigarette smoking renders plasma LDL more susceptible to subsequent peroxidative modification by cellular elements.

Adult↗
PubMedDate not supplied

Magnesium fortification of drinking water suppresses atherogenesis in male LDL-receptor-deficient mice.

Magnesium, an important cofactor of more than 300 enzymes, has previously been found to modulate blood lipid levels, atherogenesis and atherosclerosis in rabbits, when added to their diet. The aim of this study was to examine whether magnesium fortification of drinking water, without a change in diet content, can affect atherogenesis. The study included six groups of LDL-receptor-deficient mice. The mice received either distilled water or water containing 50 g of magnesium sulfate per liter. In the first (12 weeks) and second (6 weeks) stages of the experiment, the mice received low- and high-cholesterol diets, respectively. At the end of each stage, blood was drawn for the determination of plasma magnesium, calcium and lipid levels. In addition, the extent of atherosclerosis was determined at the aortic sinus. In both males and females, magnesium fortification was associated with higher levels of plasma magnesium (50 and 37% increase, respectively), without any differences in plasma calcium content. The extent of atherosclerosis at the aortic sinus in the male mice that received high levels of magnesium was a third of that of the male mice that received distilled water. However, these differences were not found in the female groups. Surprisingly, the female mice that received water fortified with magnesium had higher levels of cholesterol after stage 2, whereas no differences regarding plasma lipid levels were found among the male mice. These results confirm that magnesium fortification of drinking water is capable of inhibiting atherogenesis in male LDL-receptor-deficient mice. The mechanisms of action are yet to be discovered, and are probably not related to diminished lipid excretion, but possibly to the prevention of calcium influx into vascular smooth muscle cells, elevated antioxidative capacity, or other yet undetermined mechanisms.

Animals↗
PubMedDate not supplied

Suppression of atherogenesis in female low-density lipoprotein receptor knockout mice following magnesium fortification of drinking water: the importance of diet.

OBJECTIVE: Magnesium (Mg) has previously been found to modulate blood lipid levels, atherogenesis and atherosclerosis in rabbits when used as a dietary supplement. In addition, we have reported that Mg fortification of drinking water can attenuate atherogenesis in male low-density lipoprotein (LDL)-receptor-deficient mice, but had a mild and nonsignificant effect on female mice fed a high-cholesterol diet supplemented with cholic acid. The aim of this study was to examine whether Mg has an antiatherogenic effect in female mice fed a high-cholesterol diet without cholic acid. METHODS: Two groups of female LDL-receptor-deficient mice were included. The mice received either distilled water or water with 50 g of Mg sulfate per liter. In the first (12 weeks) and second (6 weeks) stages of the experiment, the mice received low- and high-cholesterol diets, respectively, both without cholic acid. At the end of each stage of the experiment, blood was drawn for the determination of plasma Mg, calcium and lipid levels. In addition, the extent of atherosclerosis was determined at the aortic sinus level. RESULTS: Mg fortification was associated with higher levels of plasma Mg while the mice were on a high-cholesterol diet, and the extent of atherosclerosis at the aortic sinus was significantly decreased in the female mice that received high levels of Mg compared with the female mice that received distilled water. The female mice that received water fortified with Mg had lower levels of triglycerides after stage 2, whereas no differences regarding cholesterol levels were found. CONCLUSION: These results confirm that Mg fortification of drinking water is capable of inhibiting atherogenesis also in female LDL-receptor-deficient mice fed a high-cholesterol diet, and demonstrate the importance of the nutritional composition of diet in this experimental model.

Animals↗