Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: role of Nrf2 activation.

BACKGROUND: Oxidative stress-induced vascular endothelial cell injury is a major factor in the pathogenesis of atherosclerosis. Several evidences indicate that ellagic acid (EA), a phenolic compound, contributes to cardiovascular health. This study was to investigate the effects of EA on endothelial dysfunction and atherosclerosis via antioxidant-related mechanisms. METHODS: In animal studies, wild-type (WT) C57BL/6 mice and apolipoprotein E-deficient mice (ApoE(-/-)) mice were fed: a high-fat (21%) diet (HFD) or a HFD plus with EA (HFD+EA), for 14weeks. Vascular reactivity was studied in mice aortas. The effect of EA in human umbilical vein endothelial cells (HAECs) exposed to hypochlorous acid (HOCl) was also investigated. RESULTS: Compared with animals on HFD alone, EA attenuated atherosclerosis in WT mice. In aortic rings from two mice models, EA significantly improved endothelium-dependent relaxation and attenuated HOCl-induced endothelial dysfunction. Besides, EA significantly improved nitric oxide synthase activity, antioxidant capacity and markers of endothelial dysfunction in plasma. Western blot analysis showed that EA increased NF-E2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) expression in the aortas (P<0.05). In a separate experiment, EA did not protect against HOCl-induced endothelial dysfunction in arteries obtained from Nrf2 gene knockout mice compared with WT mice. In HAECs, EA prevented HOCl-induced cellular damage and induced HO-1 protein expression, and these effects markedly abolished by the siRNA of Nrf2. CONCLUSIONS: Our results provide further support for the protective effects of dietary EA particularly oxidant-induced endothelial dysfunction and atherosclerosis partly via Nrf2 activation.

Omega-3 fatty acids do not improve endothelial function in virologically suppressed HIV-infected men: a randomized placebo-controlled trial.

Omega-3 fatty acids decrease cardiovascular disease (CVD) mortality possibly due to antiinflammatory effect. Inflammation and endothelial dysfunction likely play a role in the heightened CVD risk in HIV. Our goal was to evaluate the effect of omega-3 fatty acids primarily on endothelial function and inflammation in HIV-infected adults with moderate CVD risk on stable antiretroviral therapy. We conducted a 24-week, randomized, double-blind, placebo-controlled study to evaluate the effect of omega-3-acid ethyl esters 1 g twice a day. Flow-mediated dilation (FMD) of the brachial artery, lipoproteins and markers of inflammation, endothelial activation, coagulation, and insulin resistance were measured at entry and week 24. There were no within- or between-group differences in change in FMD over 24 weeks (mean change in FMD -0.13% vs. 1.5% for treatment vs. placebo; p=0.21). There were no between-group differences in changes in lipoprotein levels or biomarkers tested, except soluble tumor necrosis factor receptor-I, which favored omega-3-acid ethyl esters. Omega-3 fatty acids did not improve endothelial function or activation, coagulation, or insulin resistance in virologically suppressed, HIV-infected men with moderate CVD risk; however, inflammation tended to improve. This suggests that omega-3 fatty acids may not be potent enough to counteract the enhanced inflammation and endothelial dysfunction due to HIV and antiretrovirals.

[Why should vascular patients have a dietary assessment?]. / Pourquoi devons-nous évaluer l'alimentation des sujets à risque vasculaire ?

Vascular diseases are a major health problem in Western countries. Coronary heart disease (CHD), stroke, and peripheral arterial disease (PAD) share many common risk factors such as age, smoking, dyslipidemia, and diabetes. Although the dietary pattern is considered as a risk factor for CHD, the impact of dietary pattern on stroke and PAD is debated. However, new studies showed that dietary pattern could also be considered as a risk factor in stroke and PAD. Dietary pattern should be evaluated in vascular patients and new tools of dietary assessment must be developed for a better prevention of vascular disease.

Plasma fibrinogen concentration in pediatric patients treated with an elimination diet based on soy proteins and casein hydrolyzate.

PURPOSE: Fibrinogen is one of the most discussed new risk factors of atherosclerosis. The aim of the study was to assess the relationship between fibrinogen concentration and classic risk markers of atherosclerosis in a group of children aged from 2 to 6 with or without a family history of circulatory system diseases (FHCAD) (American Academy of Pediatrics--AAP criteria). The study also considered the impact of allergies/food intolerance treatment with elimination diets on the concentration of atherosclerosis markers specially fibrinogen. INCLUSION CRITERIA: a) family history of early occurrence of circulatory system diseases (FHCAD+) according to AAP standards; b) the type and duration of elimination diet continued in infancy and early childhood. 134 of 388 children were included in the investigation. RESULTS: The analysis of data relating to the so-called classic biochemical risk factors of atherosclerosis (total cholesterol--TC, HDL, LDL, triglycerides, glucose) did not reveal any differences between the tested groups. It was found that in the FHCAD+ group the concentration of fibrinogen was statistically higher than in the group with a negative family history. It was discovered that the type of elimination diet had no effect on fibrinogen level in the FHCAD+ group. In the group of children with negative family history the concentration of fibrinogen was statistically lower in the group on casein hydrolysate than in children treated with soy formula. CONCLUSIONS: The initial interview in pediatrics should include information on the patient's family history of atherosclerosis. In case of a positive family history, fibrinogen, as one of atherosclerosis risk factors, should be monitored.

Weight loss associated with reduced intake of carbohydrate reduces the atherogenicity of LDL in premenopausal women.

The effect of a 3-tier intervention including dietary modifications (ie, moderate energy restriction, decreased carbohydrate, increased protein), increased physical activity, and the use of carnitine as a dietary supplement was evaluated on plasma lipids and the atherogenicity of low-density lipoprotein (LDL) particles in a population of overweight and obese premenopausal (aged 20-45 years) women. Carnitine or a placebo (cellulose) was randomly assigned to the participants using a double-blind design. Carnitine supplementation was postulated to enhance fat oxidation resulting in lower concentrations of plasma triglycerides. Seventy women completed the 10-week protocol, which followed a reduction in their energy intake by 15% and a macronutrient energy distribution of 30% protein, 30% fat, and 40% carbohydrate. In addition, subjects increased the number of steps taken per day by 4500. As no differences were observed between the carnitine and placebo groups in all the measured parameters, all subjects were pooled together for statistical analysis. Participants decreased (P<.01) their caloric intake (between 4132.8 and 7770 kJ) and followed prescribed dietary modifications as assessed by dietary records. The average number of steps increased from 8950+/-3432 to 12764+/-4642 (P<.001). Body weight, plasma total cholesterol, LDL cholesterol, and triglyceride were decreased by 4.5%, 8.0%, 12.3%, and 19.2% (P<.0001), respectively, after the intervention. Likewise, apolipoproteins B and E decreased by 4.5% and 15% (P<.05) after 10 weeks. The LDL mean particle size was increased from 26.74 to 26.86 nm (P<.01), and the percent of the smaller LDL subfraction (P<.05) was decreased by 26.5% (P<.05) after 10 weeks. In addition, LDL lag time increased by 9.3% (P<.01), and LDL conjugated diene formation decreased by 23% (P<.01), indicating that the susceptibility of LDL to oxidation was decreased after the intervention. This study suggests that moderate weight loss (<5% of body weight) associated with reduced caloric intake, lower dietary carbohydrate, and increased physical activity impacts the atherogenicity of LDL.

Dietary copper supplements modulate aortic superoxide dismutase, nitric oxide and atherosclerosis.

The objective was to test the hypothesis that dietary copper inhibits atherosclerosis by inducing superoxide dismutase (SOD) and potentiating nitric oxide (NO). New Zealand White rabbits were fed either a cholesterol diet (n = 8) or a cholesterol diet containing 0.02% copper acetate (n = 8) for 13 weeks. We found that the intimal area was significantly smaller in the animals supplemented with copper (P < 0.005), although integrated plasma cholesterol levels were not significantly different. This was associated with a significant increase in aortic copper content (P < 0.05), SOD activity (P < 0.05) and Cu/Zn SOD mRNA (P < 0.05) and a significant decrease in nitrotyrosine content (P < 0.05). Furthermore, there was a positive correlation between aortic copper content and SOD activity (P < 0.005, R(2) = 0.83) and a negative correlation between aortic superoxide dimutase activity and nitrotyrosine content (P < 0.005, R(2) = 0.93). In organ bath experiments, the relaxation of precontracted carotid artery rings to calcium ionophore was greater in animals supplemented with copper. No difference in response to sodium nitroprusside was observed. These data suggest that in the cholesterol-fed rabbit, copper supplements inhibit the progression of atherosclerosis by increasing SOD expression, thereby reducing the interaction of NO with superoxide, and hence potentiating NO-mediated pathways that may protect against atherosclerosis.

The case for dietary calcium restriction in patients with atherosclerosis.

An increasingly vast set of data is linking the process of vascular calcification to the metabolism of calcium and phosphorus. This phenomenon is already relatively well understood in renal failure patients. A similar phenomenon, however, could be taking place in the general population. This may indicate a need for a reassessment of calcium supplementation, including the ingestion of milk, not only in dialysis patients, but also in patients with preserved renal function. Given the fact that no clear prospective randomized evidence exists to show what may be the impact on prognosis of patients with atherosclerosis, caused by the ingestion of milk and milk derivatives, containing calcium and lactose, as is currently recommended to prevent bone disease in the general population, a case could be made to recommend restriction of such dietary products in atherosclerosis patients, until precise data have been obtained, in controlled, prospective studies, and especially so in patients with no evidence of osteoporosis. Such a case would not be a strong one at the present stage, but neither would be the opposite view. The recommendation that could be made at this stage would be that patients with significant atherosclerotic disease should be informed that the ingestion of milk, and calcium supplementation in general, has neither been conclusively proven to be safe, nor the opposite.

Effect of low dose atorvastatin versus diet-induced cholesterol lowering on atherosclerotic lesion progression and inflammation in apolipoprotein E*3-Leiden transgenic mice.

OBJECTIVE: To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)-Leiden mice beyond its cholesterol-lowering effect. METHODS AND RESULTS: ApoE*3-Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet feeding was continued or mice received HC supplemented with 0.002% (w/w) atorvastatin (HC+A), resulting in 19% plasma cholesterol lowering, or mice received a low-cholesterol (LC) diet to establish a plasma cholesterol level similar to that achieved in the HC+A group. HC+A and LC diet reduced, significantly and to the same extent, lesion progression and complication in the aortic root, as assessed by measuring total atherosclerotic lesion area, lesion severity, and macrophage and smooth muscle cell area. In the aortic arch, HC+A but not LC blocked lesion progression. HC+A and LC reduced vascular inflammation (ie, expression of macrophage migration inhibitory factor , plasminogen activator inhibitor- 1, matrix metalloproteinase-9), but HC+A additionally suppressed vascular cell adhesion molecule-1 expression and, in parallel, monocyte adhesion. In contrast, low-dose atorvastatin showed no antiinflammatory action toward hepatic inflammation markers (serum amyloid A, C-reactive protein [CRP]) in apoE*3-Leiden mice and human CRP transgenic mice. CONCLUSIONS: Low-dose atorvastatin cholesterol-dependently reduces lesion progression in the aortic root but shows antiinflammatory vascular activity and tends to retard atherogenesis in the aortic arch beyond its cholesterol-lowering effect.

Apolipoprotein E promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels.

OBJECTIVE: The mechanisms by which apolipoprotein E (apoE) can promote the regression of atherosclerosis are not well understood. This study examined whether apoE can promote atherosclerosis regression independently of lowering plasma cholesterol levels. METHODS AND RESULTS: We studied hypomorphic apoE mice (Apoe(h/h)), which express an apoE4-like form of mouse apoE at approximately 2% to 5% of normal levels in plasma and are normolipidemic. After 18 weeks of diet-induced hypercholesterolemia, which resulted in advanced aortic atherosclerotic lesions composed of a lipid-rich layer of foam cells covering a fibrotic core, 2 groups of mice were fed a chow diet for 16 weeks. One group continued to express low levels of apoE; the other was induced to express physiological levels of plasma apoE by Cre-mediated recombination of the hypomorphic Apoe allele. In both groups, plasma cholesterol levels fell rapidly to similar levels, and histological analysis at 16 weeks revealed elimination of the foam-cell layer. However, physiological levels of plasma apoE also enhanced the removal of neutral lipids from the fibrotic cores. CONCLUSIONS: These findings demonstrate for the first time that apolipoprotein E promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels. Using Apoeh/hMx1-Cre mice we have begun to address apolipoprotein E-mediated mechanisms of atherosclerosis regression. We report the existence of a cholesterol-independent role of apolipoprotein E in atherosclerosis regression. This mechanism is critical for lipid removal from the fibrotic component of the plaque but not from the foam cell-rich layer beneath the endothelium.

Conjugated linoleic acid isomer effects in atherosclerosis: growth and regression of lesions.

Conjugated linoleic acid (CLA), a mixture of positional and geometric isomers of octadecadienoic acid, has been shown to inhibit experimentally induced atherosclerosis in rabbits and also to cause significant regression of pre-established atheromatous lesions in rabbits. The two major CLA isomers (cis9,trans11 and trans10,cis12), now available at 90% purity, have been tested individually for their anti-atherogenic or lesion regression potency. The two major isomers and the mixture were fed for 90 d to rabbits fed 0.2% cholesterol. Atherosclerosis was inhibited significantly by all three preparations. The two CLA isomers and the isomer mix were also fed (1.0%) as part of a cholesterol-free diet for 90 d to rabbits bearing atheromatous lesions produced by feeding an atherogenic diet. A fourth group was maintained on a cholesterol-free diet. On the CLA-free diet atherosclerosis was exacerbated by 35%. Reduction of severity of atheromatous lesions was observed to the same extent in all three CLA-fed groups. The average reduction of severity in the three CLA-fed groups was 26 +/- 2% compared with the first control (atherogenic diet) and 46 +/- 1% compared with the regression diet. Insofar as individual effects on atherosclerosis were concerned, there was no difference between the CLA mix and the cis9,trans11 and trans10,cis12 isomers. They inhibit atherogenesis by 50% when fed as a component of a semipurified diet containing 0.2% cholesterol; and when fed as part of a cholesterol-free diet, they reduce established lesions by 26%. Reduction of atheromata to the observed extent by dietary means alone is noteworthy.

A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid arteries.

OBJECTIVES: The object of this study was to assess the effects of menopause and a diet/exercise intervention on subclinical atherosclerosis progression. BACKGROUND: Subclinical atherosclerosis has been linked to higher coronary heart disease and stroke rates and is greater among postmenopausal women according to cross-sectional analyses. Whether menopause is associated with an accelerated progression of subclinical disease is unknown, as is the extent to which lifestyle intervention can alter the course of progression. METHODS: Intima-media thickness (IMT) measures of the common carotid artery (CCA), internal carotid artery (ICA), and bulb segments of the carotid arteries were measured twice during the course of 4 years in 353 women from the Women's Healthy Lifestyle Project, a dietary and exercise clinical trial designed to prevent adverse risk factor changes through the menopause. A third measure was obtained 2.5 years later for 113 women. RESULTS: The progression of IMT was observed for the average of all segments (AVG), the CCA, and the bulb (0.007 mm/year, 0.008 mm/year, and 0.012 mm/year; p < 0.01 for all), but not for the ICA. Among controls, menopause was associated with accelerated IMT progression (0.003 mm/year for premenopausal women vs. 0.008 mm/year for perimenopausal/postmenopausal women for AVG IMT; p = 0.049). Additionally, among the 160 perimenopausal/postmenopausal women, the intervention slowed IMT progression (0.008 mm/year for the control group vs. 0.004 mm/year for the intervention group for AVG IMT; p = 0.02). Similar results were found for the CCA and bulb segments. CONCLUSIONS: These data demonstrate that the menopause transition is associated with accelerated subclinical atherosclerosis progression and that a diet/exercise intervention slows menopause-related atherosclerosis progression.

Increased alpha-linolenic acid intake lowers C-reactive protein, but has no effect on markers of atherosclerosis.

OBJECTIVE: To investigate the effects of increased alpha-linolenic acid (ALA)-intake on intima-media thickness (IMT), oxidized low-density lipoprotein (LDL) antibodies, soluble intercellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP), and interleukins 6 and 10. DESIGN: Randomized double-blind placebo-controlled trial. SUBJECTS: Moderately hypercholesterolaemic men and women (55 +/- 10 y) with two other cardiovascular risk factors (n = 103). INTERVENTION: Participants were assigned to a margarine enriched with ALA (fatty acid composition 46% LA, 15% ALA) or linoleic acid (LA) (58% LA, 0.3% ALA) for 2 y. RESULTS: Dietary ALA intake was 2.3 en% among ALA users, and 0.4 en% among LA users. The 2-y progression rate of the mean carotid IMT (ALA and LA: +0.05 mm) and femoral IMT (ALA:+0.05 mm; LA:+0.04 mm) was similar, when adjusted for confounding variables. After 1 and 2 y, ALA users had a lower CRP level than LA users (net differences -0.53 and -0.56 mg/l, respectively, P < 0.05). No significant effects were observed in oxidized LDL antibodies, and levels of sICAM-1, interleukins 6 and 10. CONCLUSIONS: A six-fold increased ALA intake lowers CRP, when compared to a control diet high in LA. The present study found no effects on markers for atherosclerosis. SPONSORSHIP: The Dutch 'Praeventiefonds'.

Atherosclerosis in the apolipoprotein-E-deficient mouse: a decade of progress.

Arguably the most critical advancement in the elucidation of factors affecting atherogenesis has been the development of mouse models of atherosclerosis. Among available models, the apolipoprotein E-deficient (apoE-/-) mouse is particularly popular because of its propensity to spontaneously develop atherosclerotic lesions on a standard chow diet. A Medline search reveals over 645 articles dedicated to studies using this reliable and convenient "super" animal model since its inception (Piedrahita JA et al, Proc Natl Acad Sci U S A 1992;89:4471-4475; Plump AS et al, Cell 1992;71:343-353) with a more or less steady increase from year to year. This review will examine our present understanding of the pathology and progression of plaques in this animal and highlight some of the nutritional, pharmacological, and genetic studies that have enhanced this understanding.

O papel das estratégias de mudanças do estilo de vida para a redução de eventos ateroscleróticos / The role of lifestyle changes strategies for atherosclerotic events reduction

Neste artigo, a autora avalia as estratégias de mudança do estilo de vida para redução do risco de eventos cardiovasculares. Inicialmente, situa a doença ateroscierótíca (DAC) e seus principais eventos infarto do miocárdio e acidente vascular cerebral como as principais causas de morte no mundo ocidental, que aumentam anualmente, sendo considerada a doença ateroscierótica uma doença da vida moderna. Neste sentido, realiza ampla revisão bibliográfica mencionando as diretrizes e metas da Sociedade Brasileira de Cardiologia-Departamento de Aterosolerose. Em seguida, nas estratégias de mudança do estilo de vida, menciona o abandono do tabagismo, os benefícios terapêuticas da atividade física e a importância da dieta, apresentando amplos dados bibliográficos com referência à modificação do perfil lipídico e da função endotelial e suas aplicações clínicas. Na discussão, apresenta resultados favoráveis e outras publicações sobre a associação entre o exercício físico e o risco do desenvolvimento da DAC, comprovando a necessidade da promoção da atividade física como prioridade da saúde pública. Com relação à terapêutica dietética, salienta a importância das fibras (soluvéis e insolúveis) e suas fontes, bem como as recomendações das quantidades nos Estados Unidos da América do Norte. Menciona o mecanismo de ação das fibras e os dados epidemiológicos que relacionam sua ingestão com a diminuição da incidência de coronariopatias, bem como ações da fibra dietática sobre a redução dos níveis de lipídeos (colesterol) e também a importância das fibras na terapêutica das dislipidemias, sendo atualmente reconhecidas como alimentos funcionais.

Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E.

INTRODUCTION: This review focuses on the process of arteriosclerosis arising from oxidative stress on lipoproteins and the general failure of randomized human trials using vitamins to retard this process. REVIEW: As well as clinical trials, the paper reviews the mechanisms by which a variety of oxidants act. Antioxidants are discussed, emphasizing interactions of vitamins C and E with transition metals that can lead to prooxidation. There is a focus on interactions between supplemental or co-antioxidants that counterbalance prooxidant effects of one another. CONCLUSIONS: It is concluded that normal cellular supplementation mechanisms are poorly accessible in the arteriosclerotic plaque leading to a prooxidant environment in which the haphazard introduction of vitamins could potentially be hazardous. Continued investigations into basic and clinical redox interactions of the kind discussed in this review using new measuring techniques may lead to approaches whereby antioxidants can be introduced into tissue in controlled ways for reducing arteriosclerosis.

Soy proteins reduce progression of a focal lesion and lipoprotein oxidiability in rabbits fed a cholesterol-rich diet.

The effects of different dietary proteins on the progression of a focal atheromatous lesion and on lipoprotein oxidiability were studied in male New Zealand rabbits. Focal lesions were induced on common carotid arteries by applying an electric current, using a bipolar microcoagulator. After surgery, animals were fed for 90 days two different diets, both with 1% cholesterol, 15% saturated fatty acids and 20% protein: the protein source was constituted in one group (SOY) by 16% soy protein isolate plus 4% milk whey proteins, in the other (CASEIN) by 16% casein plus 4% milk whey proteins. Lower levels of plasma cholesterol and triglycerides (-47 and -65%, respectively) (P < 0.05) were detected in the SOY versus the CASEIN group at the end of treatment. Cryosection analyses of the carotids, indicated a highly significant reduction (-39%; P < 0.05) in the focal lesion progression in the SOY versus the CASEIN group. Copper-mediated oxidation of low-density lipoprotein (LDL) from rabbits fed the two different diets, performed in vitro by analysis of conjugated diene formation, showed a significantly longer lag phase in the SOY (150 +/- 5 min) versus the CASEIN animals (20 +/- 3 min) (P < 0.05). These data, while confirming the well-known lipid lowering properties of soy proteins, indicate, in this animal model, a remarkable activity on a focal atheromatous lesion, possibly also linked to a powerful antioxidant activity.