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M Aviram

Publications and source records attributed to M Aviram.

At least 19 recordsLinked to original sources
PubMed2005

Trampoline use as physiotherapy for cystic fibrosis patients.

Physicians and physiotherapists who care for CF patients have recommended the use of trampolines as a physiotherapeutic tool for enhancing cardiopulmonary performance, encouraging sputum production, and improving general well-being. Despite some therapeutic and recreational benefits associated with trampoline use, papers in the general pediatric population mostly document an increased incidence of injuries, ranging from minor trauma to spinal cord injuries and even death. The aim of this review is to examine the accumulated published data regarding the use of trampolines, to assess their potential contributions and disadvantages for CF patients, and to define whether trampoline use should be recommended. An extensive search in the published medical literature retrieved approximately 60 articles that primarily dealt with trampolines, out of which only two dealt with CF. The preponderance of these articles are reports pertaining to injuries related to the use of trampolines, with only a few describing the medical, physiologic, and/or psychological benefits of trampolines. Based on the accumulated data, the presumed benefits of trampoline use for CF patients are not proven. Furthermore, the suggested benefits could be acquired using other types of exercise. Weighing the known risks of trampolines against the potential benefits that are not unique to this modality suggests that the use of trampolines for CF should not be recommended.

Adolescent↗
PubMed2005

Dietary antioxidants and paraoxonases against LDL oxidation and atherosclerosis development.

Oxidative modification of low-density lipoprotein (LDL) in the arterial wall plays a key role in the pathogenesis of atherosclerosis. Under oxidative stress LDL is exposed to oxidative modifications by arterial wall cells including macrophages. Oxidative stress also induces cellular-lipid peroxidation, resulting in the formation of 'oxidized macrophages', which demonstrate increased capacity to oxidize LDL and increased uptake of oxidized LDL. Macrophage-mediated oxidation of LDL depends on the balance between pro-oxidants and antioxidants in the lipoprotein and in the cells. LDL is protected from oxidation by antioxidants, as well as by a second line of defense--paraoxonase 1 (PON1), which is a high-density lipoprotein-associated esterase that can hydrolyze and reduce lipid peroxides in lipoproteins and in arterial cells. Cellular paraoxonases (PON2 and PON3) may also play an important protective role against oxidative stress at the cellular level. Many epidemiological studies have indicated a protective role for a diet rich in fruits and vegetables against the development and progression of cardiovascular disease. A large number of studies provide data suggesting that consumption of dietary antioxidants is associated with reduced risk for cardiovascular diseases. Basic research provides plausible mechanisms by which dietary antioxidants might reduce the development of atherosclerosis. These mechanisms include inhibition of LDL oxidation, inhibition of cellular lipid peroxidation and consequently attenuation of cell-mediated oxidation of LDL. An additional possible mechanism is preservation/increment of paraoxonases activity by dietary antioxidants. This review chapter presents recent data on the anti-atherosclerotic effects and mechanism of action of three major groups of dietary antioxidants-vitamin E, carotenoids and polyphenolic flavonoids.

Animals↗
PubMed2004

Systemic inflammatory mediators and cystic fibrosis genotype.

Morbidity and mortality in cystic fibrosis patients is mainly attributed to pulmonary infection and inflammation. Chemokines play a pivotal role in the inflammatory process. Although genotype-phenotype correlation in cystic fibrosis patients has been defined, a clear relationship between the defect in the cystic fibrosis transmembrane regulator (CFTR) gene and pulmonary inflammation has not been established. The aim of this study was to assess whether serum chemokines levels in cystic fibrosis patients correlate with genotype and pulmonary function tests, as well as with other clinical characteristics. Serum levels of interleukin-8, RANTES, and monocyte chemoattractant protein-1 were measured in 36 cystic fibrosis patients grouped according to their genotype. Group A included 25 patients who carried two mutations associated with a pathological sweat test and pancreatic insufficiency (deltaF508, W1282X, G542X, N1303K, S549R). Group B included 11 compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat test and pancreatic sufficiency (3849+10kb C to T, 5T). Associations between chemokine levels, genotype, pulmonary function, Pseudomonas aeruginosa colonization, age, sweat chloride level, and pancreatic and nutritional status were examined. Mean interleukin-8 and monocyte chemoattractant protein-1 levels were significantly higher in group A than group B (11.4 +/- 2.1 pg/ml vs. 5 +/- 0.9 pg/ml and 157 +/- 16 pg/ml vs. 88.8 +/- 16.4 pg/ml, respectively) (P < 0.01). No difference in RANTES levels were found between groups. interleukin-8 levels were inversely related to forced expiratory volume in 1 s (r = -0.37, P < 0.02), while there was no association between the latter and RANTES and monocyte chemoattractant protein-1 levels. The Pseudomonas colonization rate was higher among group A patients than group B (88% vs. 40%, P < 0.01). No relationship was found between measured chemokines and age, sweat chloride levels, and pancreatic and nutritional status. Our study demonstrates an association between interleukin-8, forced expiratory volume, and cystic fibrosis genotype. Hence, elevated interleukin-8 serum levels could serve as an indicator of an early inflammatory process and encourage the initiation of anti-inflammatory treatment.

Adolescent↗
PubMed2003

Serum CA 19-9 levels as a diagnostic marker in cystic fibrosis patients with borderline sweat tests.

Patients with normal or borderline sweat tests present a diagnostic challenge. In spite of the availability of genetic analysis and measurement of nasal potential difference, there is still uncertainty in diagnosing cystic fibrosis in some patients. CA 19-9 is a tumor-associated antigen whose levels were previously found to be elevated in some cystic fibrosis patients. We investigated whether serum CA 19-9 levels can contribute to establishing the diagnosis of cystic fibrosis in patients with a borderline sweat test, and evaluated the influence of different clinical variables on CA 19-9 levels. Serum CA 19-9 levels were measured in 82 cystic fibrosis patients grouped according to their genotype and in 38 healthy individuals. Group A included 50 patients who carried two mutations previously found to be associated with a pathological sweat test and pancreatic insufficiency (DeltaF508, W1282X, G542X, N1303K, and S549R). Group B included 13 compound heterozygote cystic fibrosis patients who carried one mutation known to cause mild disease with a borderline or normal sweat test and pancreatic sufficiency (3849+10kb C-->T, 5T). Group C included 38 normal controls. Nineteen cystic fibrosis patients carried at least one unidentified mutation. An association between CA 19-9 levels and age, pulmonary function, pancreatic status, sweat chloride, previous pancreatitis, serum lipase, meconium ileus, distal intestinal obstruction, liver disease, and diabetes was investigated. The distribution of CA 19-9 levels was significantly different between the three groups ( p<0.01); high CA 19-9 levels were found in 60% (30/50) of group Apatients and in 46.6% (6/13) of group B patients, but in only 5.2% (2/38) of the controls. CA 19-9 levels were inversely related to forced expiratory volume in 1 s, while no association was found with the other clinical parameters examined. Our findings suggest that the serum CA 19-9 in cystic fibrosis patients originates in the respiratory system, and has a useful ancillary role, particularly when diagnostic uncertainty exists. Hence, the diagnosis of cystic fibrosis should be considered in patients with borderline sweat tests and high CA 19-9 levels, but normal levels do not exclude cystic fibrosis.

Adolescent↗
PubMed2002

Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans.

The beneficial health effects attributed to the consumption of fruit and vegetables are related, at least in part, to their antioxidant activity. Of special interest is the inverse relationship between the intake of dietary nutrients rich in polyphenols and cardiovascular diseases. This effect is attributed to polyphenols' ability to inhibit low-density lipoprotein (LDL) oxidation, macrophage foam cell formation and atherosclerosis. Pomegranate polyphenols can protect LDL against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages. Pomegranate polyphenols were shown to reduce the capacity of macrophages to oxidatively modify LDL, due to their interaction with LDL to inhibit its oxidation by scavenging reactive oxygen species and reactive nitrogen species and also due to accumulation of polyphenols in arterial macrophages; hence, the inhibition of macrophage lipid peroxidation and the formation of lipid peroxide-rich macrophages. Furthermore, pomegranate polyphenols increase serum paraoxonase activity, resulting in the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions. These antioxidative and antiatherogenic effects of pomegranate polyphenols were demonstrated in vitro, as well as in vivo in humans and in atherosclerotic apolipoprotein E deficient mice. Dietary supplementation of polyphenol-rich pomegranate juice to atherosclerotic mice significantly inhibited the development of atherosclerotic lesions and this may be attributed to the protection of LDL against oxidation.

Animals↗
PubMed2001

Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure.

Consumption of pomegranate juice which is rich in tannins, possess anti-atherosclerotic properties which could be related to its potent anti-oxidative characteristics. As some antioxidants were recently shown to reduce blood pressure, we studied the effect of pomegranate juice consumption (50 ml, 1.5mmol of total polyphenols per day, for 2 weeks) by hypertensive patients on their blood pressure and on serum angiotensin converting enzyme (ACE) activity. A 36% decrement in serum ACE activity and a 5% reduction in systolic blood pressure were noted. Similar dose-dependent inhibitory effect (31%) of pomegranate juice on serum ACE activity was observed also in vitro. As reduction in serum ACE activity, even with no decrement in blood pressure, was previously shown to attenuate atherosclerosis, pomegranate juice can offer a wide protection against cardiovascular diseases which could be related to its inhibitory effect on oxidative stress and on serum ACE activity.

Aged↗
PubMed2001

Reduced susceptibility of low density lipoprotein to lipid peroxidation after cholestyramine treatment in heterozygous familial hypercholesterolemic children.

Cholestyramine treatment in children with heterozygous familial hypercholesterolemia (FHHe) can interfere with fat absorption from the intestinal tract, and has the potential to decrease the absorption of fat-soluble vitamins. The aim of this study was to examine the effect of cholestyramine treatment on the levels of the fat soluble vitamins (vitamin E, beta-carotene and lycopene) in LDL, on the glutathione system and on the susceptibility of LDL to oxidation in FHHe children. Patients were 16 children (seven girls, nine boys), age 14+/-4 years, non-smokers. Plasma LDL level before cholestyramine treatment but after dietary treatment was 239+/-50 mg% with no secondary cause for hypercholesterolemia. A control group was comprised of ten children (seven girls, three boys), age 14+/-4 years with plasma LDL level of 100+/-14 mg%. Blood was drawn from 16 FHHe children and five control children after fasting for 14 h. Thereafter cholestyramine treatment was begun in the patient group, at a dose of 8 g/day for 2 months. At the end of this period the dose was increased to 12-16 g/day for an additional 2 months. After 4 months from the beginning of the treatment, blood was drawn again. Plasma LDL cholesterol decreased after treatment by 14% (from 239+/-67 mg% before treatment to 205+/-55 mg% after treatment, P=0.07). Malondialdehyde (MDA) levels measured by thiobarbituric reactive substances (TBARS) assay in LDL at the end of oxidation were 30% higher in FHHe children in comparison to controls (P=0.02). After treatment TBARS levels in LDL (after in vitro oxidation) from FHHe children were decreased by 23% (P=0.02). Vitamin E levels in LDL from FHHe children after treatment were decreased by 65%, while beta-carotene and lycopene contents in LDL, paradoxically increased by 90 and 102%, respectively. In red blood cells (RBC), glutathione peroxidase (GPx) and glutathione transferase (GTf) activities were decreased by 29 and 24%, respectively, while glutathione reductase activity, total and oxidized glutathione contents from FHHe children did not change after cholestyramine treatment. LDL was more prone to oxidation in FHHe children than in controls, when measured by TBARS levels after LDL oxidation (with 10 &mgr;M CuSO(4)). Cholestyramine treatment for 4 months normalized LDL susceptibility to oxidation measured by TBARS levels, despite the decrease in vitamin E content in LDL from treated FHHe children. This is presumably due to the increased LDL content of beta-carotene and lycopene after treatment. GPx and GTf activities decreased after treatment, presumably due to the drop in oxidative stress within the RBCs, in parallel to the decreased LDL tendency to oxidation. Cholestyramine treatment in FHHe children has an overall antioxidant effect on LDL.

Journal Article↗
PubMed2001

White wine with red wine-like properties: increased extraction of grape skin polyphenols improves the antioxidant capacity of the derived white wine.

Lower antioxidant activity in white wines in comparison to red wines lies in the low grape-skin-derived polyphenol content. This paper reports the analysis of the antioxidant capacities of white wine samples obtained along two different processing procedures directed to enrich the wine with polyphenols. White wine samples derived from whole squeezed grapes stored for increasing periods of time (up to 18 h) contained increasing concentrations of polyphenols (from 0.35 to 0.55 mmol/L) and, in parallel, exhibited increased capacity to scavenge free radicals and to inhibit copper ion-induced low-density lipoprotein (LDL) oxidation. However, addition of increasing concentrations of alcohol (up to 18%) to the whole squeezed grapes remarkably augmented the extraction of grape skin polyphenols into the wine up to 1.25 mmol/L, resulting in an increased capacity of the wine to scavenge free radicals and to inhibit LDL oxidation, to an extent similar to that of red wine. The extent of LDL oxidation inhibition was directly related to the wine polyphenolic content (r = 0.986). It is concluded that processing white wine by imposing a short period of grape skin contact in the presence of alcohol leads to extraction of grape skin polyphenols and produces polyphenol-rich white wine with antioxidant characteristics similar to those of red wine.

Antioxidants↗
PubMed2001

Prediction of mortality and timing of referral for lung transplantation in cystic fibrosis patients.

Lung transplantation (Tx) is an optional treatment for cystic fibrosis (CF) patients with end-stage lung disease. The decision to place a patient on the Tx waiting list is frequently complex, difficult, and controversial. This study evaluated the current criteria for lung Tx and assessed additional parameters that may identify CF patients at high risk of death. Data were extracted from the medical records of 392 CF patients. Forty of these patients had a forced expiratory volume in 1 s (FEV(1)) less than 30% predicted, and nine of these 40 patients were transplanted. A comparison was performed between the survival of those transplanted (n = 9) and those not transplanted (n = 31), by means of Kaplan-Meier survival curves. The influence on survival of age, gender, nutritional status, sputum aspergillus, diabetes mellitus, recurrent hemoptysis, oxygen use, and the decline rate of FEV(1), were investigated by means of univariate and multivariate analyses. The rate of decline of FEV(1) was evaluated employing the linear regression model. CF patients with a FEV(1)< 30% and who did not receive a lung transplant had survived longer than CF patients who did receive a lung transplant (median survival 7.33 vs. 3.49 yr, 5-yr survival 73% vs. 29%). Two factors--rate of decline in FEV(1) values and age < 15 yr--were found to influence the mortality rate, while the other parameters examined did not. Our results indicate that the current criterion of FEV(1)< 30% predicted, alone is not sufficiently sensitive to predict the mortality rate in CF patients and time of referral for Tx, as many of these patients survive for long periods of time. Additional criteria to FEV(1)< 30%, should include rapidly declining FEV(1) values and age < 15 yr.

Adolescent↗
PubMed2001

Choosing an oestrogen replacement therapy in young adult women with Turner syndrome.

OBJECTIVE: Hormone replacement therapy (HRT) is prescribed to most patients with Turner syndrome (TS) although its use in adult TS patients has not been scientifically evaluated. The present study was performed to compare the short-term effects in adult women with Turner syndrome of low-dose oral conjugated oestrogen (0.625 mg, CE) with relatively high dose ethinyl oestradiol (30 microg, EE2); both combined with an oral progestin. DESIGN AND PATIENTS: After 4 months off HRT, 17 young, otherwise healthy women with TS were enrolled in a random, unblinded, crossover study of the two oestrogenic preparations, each given for 6 months. MEASUREMENTS: We compared parameters of oestrogenic activity that would cover immediate changes in hormone levels, biochemistry, bone turnover, uterine and cardiac variables, which constitute risk factors for later development of diabetes, atherosclerosis, osteoporosis and aortic dissection. RESULTS: Serum FSH returned to normal follicular phase levels only on the EE2 regimen. The hypotrophic endometria normalized with either of the two oestrogen regimens with no excessive hypertrophy. Hyperinsulinaemia was suppressed to normal by both EE2 and CE. PTH and 1,25-dihydroxyvitamin D levels increased on HRT (EE2 > CE), and phosphorus decreased. Alkaline phosphatase, osteocalcin and urinary deoxypyridinoline cross-links (DPD) were high off therapy; the former two suppressed to high-normal levels on the EE2 regimen, but not on CE, and DPD did not normalize with either HRT. Lipid profiles in these young TS patients were normal. Liver enzymes were mildly elevated off therapy and suppressed to normal levels on both regimens, but more so with EE2. CONCLUSIONS: The risk factors embodied in hyperinsulinaemia and enhanced bone turnover which, ultimately, have consequences for TS morbidity, are minimized by HRT. In the short term, neither regimen is effective for bone turnover in adult women with Turner syndrome.

Adolescent↗
PubMed2001

Selective distribution of oxysterols in atherosclerotic lesions and human plasma lipoproteins.

The presence of oxidized sterols (oxysterols) in human serum and lesions has been linked to the initiation and progression of atherosclerosis. Data concerning the origin, identity and quantity of oxysterols in biological samples are controversial and inconsistent. This inconsistency may arise from different analytical methods or handling conditions used by different investigators. In the present study, oxysterol levels and distribution were analyzed by an optimized GC-MS method, in human atherosclerotic coronary and carotid lesions, in atherosclerotic apolipoprotein E deficient mice (E degrees mice) and in native and in vitro oxidized human low and high density lipoproteins. Oxysterol levels were analyzed with a limit of detection of 0.06 - 0.24 ng, with 25-hydroxycholesterol (25-OH) being the least sensitive. In human coronary and carotid lesions, obtained from endatherectomic samples, 27-hydroxycholesterol (27-OH) was the major oxysterol, with about 85% as sterols esterified to fatty acids. While total cholesterol and oxysterols levels were similar in both kinds of human lesions, oxysterol distribution was significantly different. In coronary lesions the mean levels of 27-OH and 7beta-hydroxycholesterol (7beta-OH) were 38% and 20% of total oxysterols, whereas in carotid lesions their mean levels were 66% and 5%, respectively. Unlike in human aortic lesions, 27-OH was entirely absent in E degrees mice, whereas the level of 7alpha-hydroxycholesterol (7alpha-OH) was 28% of the total oxysterols, vs. 5% in human coronary lesions. As 27-OH is an enzymatic product of cholesterol oxidation, this finding may indicate that such an enzymatic process does not take place in E degrees mice.

Animals↗
PubMed2001

Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis.

Inhibition of lipid peroxidation contributes to the attenuation of macrophage cholesterol accumulation, foam-cell formation and atherosclerosis. Evidence suggests that nutritional antioxidants such as pomegranate juice (PJ) can contribute to the reduction of oxidative stress and atherogenesis. The goals of the present study were to determine whether such beneficial effects of PJ exist when supplemented to apolipoprotein E-deficient (E(0)) mice with advanced atherosclerosis and to analyze the antiatherosclerotic activity of a tannin-fraction isolated from PJ. Mice (4-mo-old) were supplemented with PJ in their drinking water for 2 mo and compared with age-matched placebo-treated mice, as well as to young (4-mo-old) control mice, for their mouse peritoneal macrophage (MPM) oxidative state, cholesterol flux and mice atherosclerotic lesion size. PJ supplementation reduced each of the proatherogenic variables determined in the present study compared with age-matched placebo-treated mice. It significantly induced serum paraoxonase activity and reduced MPM lipid peroxide content compared with placebo-treated mice and control mice. PJ administration to E(0) mice significantly reduced the oxidized (Ox)-LDL MPM uptake by 31% and MPM cholesterol esterification and increased macrophage cholesterol efflux by 39% compared with age-matched, placebo-treated mice. PJ consumption reduced macrophage Ox-LDL uptake and cholesterol esterification to levels lower than those in 4-mo-old, unsupplemented controls. PJ supplementation to E(0) mice with advanced atherosclerosis reduced the lesion size by 17% compared with placebo-treated mice. In a separate study, supplementation of young (2-mo-old) E(0) mice for 2 mo with a tannin fraction isolated from PJ reduced their atherosclerotic lesion size, paralleled by reduced plasma lipid peroxidation and decreased Ox-LDL MPM uptake. PJ supplementation to mice with advanced atherosclerosis reduced their macrophage oxidative stress, their macrophage cholesterol flux and even attenuated the development of atherosclerosis. Moreover, a tannin-fraction isolated from PJ had a significant antiatherosclerotic activity.

Animals↗
PubMed2001

Flavonoids protect LDL from oxidation and attenuate atherosclerosis.

Consumption of some plant-derived flavonoids results in their absorption and appearance in plasma and tissues. The inverse relationship between dietary flavonoids consumption and cardiovascular diseases may be associated with the ability of flavonoids to attenuate LDL oxidation, macrophage foam cell formation and atherosclerosis. The effect of flavonoids on arterial cell-mediated oxidation of LDL is determined by their accumulation in the lipoprotein and in arterial cells, such as macrophages. Flavonoids can reduce LDL lipid peroxidation by scavenging reactive oxygen/nitrogen species, chelation of transition metal ions and sparing of LDL-associated antioxidants. They can also reduce macrophage oxidative stress by inhibition of cellular oxygenases [such as nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase] or by activating cellular antioxidants (such as the glutathione system). Thus, plant flavonoids, as potent natural antioxidants that protect against lipid peroxidation in arterial cells and lipoproteins, significantly attenuate the development of atherosclerosis.

Antioxidants↗
PubMed2001

Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering.

Recent evidence suggests that some benefit from the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may occur independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary endothelial function, endothelial NO synthase (eNOS) expression, and oxidative stress in experimental hypercholesterolemia (HC) in the absence of cholesterol lowering. Pigs were randomized to 3 experimental groups: normal diet (N group), high cholesterol diet (HC group), and HC diet with simvastatin (HC+S group) for 12 weeks. Low density lipoprotein cholesterol was similarly increased in the HC and HC+S groups compared with the N group. In vitro analysis of coronary large- and small-vessel endothelium-dependent vasorelaxation was performed. The mean vasorelaxation of epicardial vessels to bradykinin was significantly attenuated in the HC group compared with the N group (32.3+/-1.2% versus 42.9+/-1.6%, respectively; P<0.0001). This attenuation was significantly reversed in the HC+S group (38.7+/-1.5%, P<0.005 versus HC group). The maximal vasorelaxation to substance P was significantly attenuated in the HC group compared with the N group (50.5+/-11.9% versus 79.3+/-5.3%, respectively; P<0.05). This attenuated response was normalized in the HC+S group (74.9+/-4.1%, P<0.05 versus HC group). The maximal arteriolar vasorelaxation to bradykinin was also significantly attenuated in the HC group compared with the N group (71.9+/-4.9% versus 96.8+/-1.34%, respectively; P<0.005). This was reversed in the HC+S group (98.4+/-0.6%, P<0.0001 versus HC group). Western blotting of coronary tissue homogenates for eNOS demonstrated a decrease in protein levels in the HC group compared with the N group, with normalization in the HC+S group. Elevation of plasma F(2)-isoprostanes and thiobarbituric acid-reactive substances, markers of oxidative stress, occurred in the HC compared with the N group. These changes were reversed in the HC+S group. In summary, simvastatin preserves endothelial function in coronary epicardial vessels and arterioles in experimental HC (in the absence of cholesterol lowering) in association with an increase in coronary eNOS levels and a decrease in oxidative stress. These alterations may play a role in the reduction in cardiac events after treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

Animals↗
PubMed2001

Retention of oxidized LDL by extracellular matrix proteoglycans leads to its uptake by macrophages: an alternative approach to study lipoproteins cellular uptake.

Interaction between arterial macrophages and oxidized LDL (Ox-LDL) leads to foam cell formation, a critical step during early atherogenesis. Until now, cellular uptake of lipoproteins was studied through incubation of the media-soluble lipoprotein with cultured macrophages. However, as lipoproteins in the arterial wall are bound to subendothelial matrix, we questioned whether the retention (binding) of Ox-LDL to a macrophage-derived extracellular matrix (ECM) could lead to enhanced uptake by macrophages. The uptake of ECM-bound Ox-LDL by activated macrophages (by phorbol myristate acetate) was lipoprotein dose dependent, time dependent and higher (by 1.5-fold) than the uptake of ECM-bound native LDL. Preincubation of the ECM with lipoprotein lipase before the addition of Ox-LDL was essential for the uptake of ECM-bound Ox-LDL by the macrophages. After radiolabeling of the ECM glycosaminoglycans (GAGs), we found that ECM-bound Ox-LDL is taken up by the macrophages together with the ECM-GAG. Finally, these results were further confirmed through the use of ECM obtained from mouse peritoneal macrophages (MPMs), derived from atherosclerotic, apoE-deficient mice. In 24-week-old mice with developed atherosclerosis, the GAG content of their MPM-derived ECM increased by 52%, the ability of their MPM-derived ECM to bind Ox-LDL increased by 57%, and macrophage uptake of Ox-LDL that was retained by the MPM-derived ECM increased by 86%. In conclusion, the present study demonstrated that ECM-bound Ox-LDL is taken up by activated macrophages. This may represent a physiopathological phenomenon that leads to cholesterol and oxysterol accumulation in arterial macrophages, the hallmark of early atherosclerosis.

Aging↗
PubMed2001

Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin-6.

The goal of the present study was to elucidate mechanisms for angiotensin II (Ang II) induction of oxidized low density lipoprotein (Ox-LDL) uptake by macrophages, the hallmark of early atherosclerosis. Compared with placebo treatment, Ang II injections (0.1 mL, 10(-7) mol/L per day) for 2 weeks to apolipoprotein E-deficient mice significantly increased Ox-LDL degradation, CD36 mRNA expression, and CD36 protein expression by their peritoneal macrophages (MPMs). These effects were abolished by treatment with losartan (5 to 50 mg/kg per day) before Ang II administration. Because no such effect was obtained in vitro, the ex vivo effect of Ang II on macrophage uptake of Ox-LDL could be mediated by a factor that is not expressed at a significant level in vitro. Because Ang II stimulates cellular production of interleukin-6 (IL-6), we analyzed the possible role of IL-6 as a mediator of Ang II-mediated cellular uptake of Ox-LDL by using several approaches. First, incubations of IL-6 with MPM or IL-6 administration in mice increased macrophage Ox-LDL degradation and CD36 mRNA expression. Second, injection of IL-6 receptor antibodies in mice during Ang II treatment reduced macrophage Ox-LDL uptake and CD36 expression compared treatment with Ang II alone. Finally, Ang II treatment of IL-6-deficient mice did not affect their MPM Ox-LDL uptake and CD36 protein levels. Thus, we conclude that a novel mechanism for Ang II atherogenicity, related to macrophage cholesterol accumulation and foam cell formation, may involve its stimulatory effect on macrophage uptake of Ox-LDL, a process mediated byIL-6.

Angiotensin II↗
PubMed2001

Anti-atherogenicity of nutritional antioxidants.

Epidemiological studies have indicated that fruit- and vegetable-rich diets play a protective role against cardiovascular disease. An explanation for this protection lies in the presence of antioxidant vitamins in fruits and vegetables. A large number of studies have provided data suggesting that consumption of dietary antioxidants is associated with reduced risk for cardiovascular disease. Plausible mechanisms by which these antioxidants may reduce the development of atherosclerosis include inhibition of low-density lipoprotein (LDL) oxidation, cellular lipid peroxidation and cell-mediated oxidation of LDL, and reduction in blood cholesterol levels. This review reports on the recent data of the anti-atherosclerotic effects and mechanistical aspects of three major groups of dietary antioxidants: vitamin E, carotenoids and flavonoids.

Journal Article↗