Reduced Homocysteine Concentrations Research Articles

Endothelio- and cardioprotective effects of vitamin в6 and folic acid in modelling methionine-induced hyperhomocysteinemia

The endotelio- and cardioprotective effects of vitamin B6 (2 mg/kg) and folic acid (0.2 mg/kg) upon modeling of methionine-induced hyperhomocysteinemia via methionine intragastric administration at a dose of 3 g/kg were studied. It was shown that the combined use of vitamin B6 and folic acid allows on the background of a significant reduction in homocysteine concentrations normalizing the endothelial dysfunction coefficient and the parameters of maximum left ventricular pressure in response to intravenous administration of adrenaline. The research was partially supported by the grant of the President of the Russian Federation №MD-4711.2015.7.

Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults.

Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults.

Dietary betaine reduces plasma homocysteine concentrations and improves bone strength in laying hens

ABSTRACT 1. This study tested the hypothesis that the methyl-donor properties of betaine could reduce homocysteine concentrations, which has been recognised in a previous genetics study to be linked to bone quality. This was combined with phytase treatment, as phosphorus is critical for bone mineralisation. 2. Using a 2 × 2 factorial arrangement, a total of 1920 Lohmann LSL-lite chickens housed as 24 replicates of 20 chickens were fed one of four diets containing dietary betaine (0 or 1000 mg/kg) and phytase (300 or 1000 FTU/kg) from one day old until end-of-lay. Blood and bone samples were collected at 45 and 70 weeks of age. 3. Hens fed betaine had lower plasma homocysteine level (P < 0.05), higher tibia breaking strength (P < 0.05) and higher tibia bone density (P < 0.05). 4. Egg production and quality was excellent throughout the study and were not affected by the dietary treatments. 5. The addition of dietary betaine was successful at reducing plasma homocysteine concentrations and improving bone strength in laying hens, which could be used as an intervention to alleviate welfare concerns.

Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults

Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults

Fruit and vegetables consumption is associated with higher vitamin intake and blood vitamin status among European adolescents.

Current research in adults indicates that fruit and vegetable (FAV) consumption increases serum levels of vitamins C, E and folate of β-carotene and reduces homocysteine concentrations. The aim of the present study was to examine the association of FAV consumption on vitamin intakes and their impact on blood vitamin concentrations in European adolescents. This multi-center cross-sectional study included 702 (53.7% females) adolescents, aged 12.50-17.49 years, from 10 European cities. Two independent self-administered 24 h dietary recalls were used to estimate the adolescent's diet. The total energy, vitamins and FAV consumption were calculated. Adolescents were categorized into three groups: (i) very low FAV intake (<200 g/day); (ii) low FAV consumption (200-399 g/day) and (iii) adequate FAV consumption (⩾400 g/day). Adolescent's fasted blood samples were taken for their analysis on vitamin concentrations. The main results showed that those adolescents meeting the FAV recommendation, classified as FAV adequate consumers, presented higher intake of energy and some vitamins as B6, total folic acid, C, E and β-carotene compared with FAV very low consumers (P<0.05). Regarding their blood status, male adolescents who had a very low FAV consumption presented lower plasma folate, RBC folate blood concentrations compared with adequate FAV consumers (P<0.05). Female adequate FAV consumers had higher concentrations of pyridoxal phosphate (PLP), plasma folate, RBC folate, vitamin C, β-carotene and α-tocopherol compared with very low and low consumers (P<0.05). Having a FAV dairy intake above 400 g/day is associated with higher vitamin intake and blood vitamin concentrations, especially for antioxidant and B-vitamins concentrations.

Proteína C reactiva y homocisteína en menopáusicas tratadas con tibolona

ObjectiveTo determine modifications in C-reactive protein and homocysteine in postmenopausal women who used tibolone. Materials and methodsWe selected a sample of 45 postmenopausal women treated with a 2.5-mg dose of tibolone daily for 6 months. Serum concentrations of C-reactive protein and homocysteine were measured. ResultsC-reactive protein concentrations were significantly increased after 6 months of treatment (0.51±0.29mg/dl at baseline compared with 0.95±0.34mg/dl after treatment; P<.05). Homocysteine concentrations were significantly reduced after 6 months of treatment (10.16±1.45picomol/L) compared with initial values (10.95±1.87picomol/L; P<.05). ConclusionsAfter 6 months of use, tibolone significantly increased C-reactive protein concentrations and reduced homocysteine concentrations.

Increased systolic blood pressure in rat offspring following a maternal low-protein diet is normalized by maternal dietary choline supplementation.

An adverse prenatal environment may induce long-term metabolic consequences, in particular hypertension and cardiovascular disease. A maternal low-protein (LP) diet is well known to result in increased blood pressure (BP) in offspring. Choline has been shown to have direct BP-reducing effects in humans and animals. It has been suggested that endogenous choline synthesis via phosphatidylcholine is constrained during maternal LP exposure. The present study investigates the effect of choline supplementation to mothers fed a LP diet during pregnancy on systolic BP (SBP) in offspring as measured by tail-cuff plethysmography. Wistar rats were assigned to one of three diets to be fed ad libitum throughout pregnancy: (1) control diet (CONT, 20% protein); (2) an LP diet (9% protein); and (3) LP supplemented with choline (LP + C). Dams were fed the CONT diet throughout lactation and offspring were fed the CONT diet from weaning for the remainder of the trial. At postnatal day 150, SBP and retroperitoneal fat mass was significantly increased in LP offspring compared with CONT animals and was normalized in LP + C offspring. Effects of LP + C reduction in SBP were similar in both males and females. Plasma choline and phosphatidylcholine concentrations were not different across treatment groups, but maternal choline supplementation resulted in a significant reduction in homocysteine concentrations in LP + C offspring compared with LP and CONT animals. The present trial shows for the first time that maternal supplementation with dietary choline during periods of LP exposure can normalize increased SBP and fat mass observed in offspring in later life.

Folic Acid and Vitamin B12 Fortification of Flour: A Global Basic Food Security Requirement

Folic acid is an essential water soluble B vitamin which has been used for decades in the prevention of folate deficiency anemia of pregnancy. In 1991, folic acid taken prior to the start of pregnancy was shown unequivocally to prevent spina bifida and anencephaly—two of the most serious and common birth (neural tube) defects. Soon governments recommended that women of reproductive age consume folic acid daily to prevent these birth defects. Because compliance was low and since more than half of pregnancies are unplanned, the United States Food and Drug Administration mandated in 1998 that all enriched flour be fortified with folic acid at a concentration estimated to give the average woman an intake of 100 micrograms of folic acid a day. Canada and Chile followed with similar requirements for folic acid fortification of wheat flour. Now there is mandatory fortification in more than 50 countries globally. Where fortification has been implemented and studied, it has led to dramatic increases in serum folate concentrations, reduction in neural tube defects, folate deficiency anemia, as well as the reduction in homocysteine concentrations and stroke mortality with no known risk. Australia implemented mandatory folic acid fortification in 2009. To date, no country in Europe has implemented mandatory folic acid fortification of flour, although it has been recommended by the UK Food Safety Authority. This review discusses the vital importance of mandatory flour fortification with folic acid and vitamin B12, for public health food security and as a challenge to the New Public Health in Europe and globally.

Low-dose folic acid supplementation reduces homocysteine concentration in hyperhomocysteinemic coronary artery disease patients

Whether patients with coronary artery disease need to supplement their diet with a high dose of folic acid (even if their folate status is adequate) to reduce their plasma homocysteine concentration remains unclear. The purpose of this study was to evaluate the effect of a low oral dose of folic acid on lowering the plasma homocysteine concentration in response to the 5,10-methylenetetrahydrofolate reductase 677→T genotypes in patients with coronary artery disease. Patients were randomly assigned to 1 of 2 groups: a placebo group (n = 22; CC/CT/TT = 12/7/3) and a folic acid group (400 μg/d folate; n = 24; CC/CT/TT = 8/11/5). Intervention was administered for 2 months (8 weeks). Folic acid supplements did not significantly lower fasting plasma homocysteine concentration after 8 weeks of supplementation. However, low-dose folic acid supplementation (400 μg/d) significantly reduced homocysteine by 1.8 μmol/L ( P < .05) at week 8 for those subjects with hyperhomocysteinemia, especially for carriers of the T-allele.

Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis

Some subjects with multiple sclerosis (MS) present with low blood iron parameters. Anecdotal reports and a single patient study suggest that iron supplementation may be beneficial in these subjects. Myelin is regenerated continually, but prerequisites for this process are iron and a functional folate-vitamin B12-methylation pathway. The aim of this study was to determine iron status, folate and homocysteine in MS subjects, and to evaluate the effect on MS symptoms if deficiencies were addressed. In relapsing-remitting MS subjects, serum iron concentration correlated significantly with age at diagnosis (r=0.49; p=0.008). In Caucasian female MS subjects, serum iron and ferritin concentrations were significantly lower than in matched controls. In a 6-month pilot study, 12 subjects taking a regimen of nutritional supplements designed to promote myelin regeneration, improved significantly neurologically as measured by the Kurzke EDSS (Total Score means 3.50 to 2.45, 29.9%; p=0.021). These were significantly improved (p=0.002) compared to 6 control group patients taking multivitamins (Kurzke Score increased by 13.9% from 4.83 to 5.50). Both groups had significantly reduced homocysteine concentrations at 6 months, suggesting that methylation is necessary but not sufficient for myelin regeneration.

Responsiveness of homocysteine concentrations to food and supplemental folate intakes in smokers and never‐smokers enrolled in a diet intervention trial

We investigated circulating homocysteine concentrations in relation to smoking, folate intake (from food and supplements), serum folate concentrations, and other dietary variables. The present study is part of a parent trial assessing the effects of increasing vegetable, fruit, and fiber intakes and reducing the percentage of energy obtained from fat on breast cancer recurrence in 3,088 women previously diagnosed with breast cancer. Of the 121 smokers enrolled in the parent trial, 85 were available at baseline for the present study and were randomly matched to 85 never-smokers on baseline folate intake, age, and intervention status. Follow-up data were available on 53 smokers (22 intervention and 31 comparison) and 56 never-smokers (24 intervention and 32 comparison). No significant differences in circulating homocysteine and folate concentrations were observed between smokers and never-smokers at baseline. For smokers, significant decreases in circulating homocysteine and significant increases in folate concentrations (p < .05) from baseline to 12 months were observed in the comparison group. For never-smokers, significant decreases in circulating homocysteine and significant increases in folate concentrations were observed in the intervention and comparison groups (p < .05). In the multivariate analysis, changes in serum folate concentration and supplemental folic acid were significantly associated with change in plasma homocysteine concentrations (p < .05). These findings show that increasing supplemental folic acid can reduce homocysteine concentrations, which may have implications for lowering cardiovascular disease risk for smokers and never-smokers.

Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials

Dietary supplementation with B vitamins that lower blood homocysteine concentrations is expected to reduce cardiovascular disease risk, but there has been uncertainty about the optimum regimen to use for this purpose. The objectives were to ascertain the lowest dose of folic acid associated with the maximum reduction in homocysteine concentrations and to determine the additional relevance of vitamins B-12 and B-6. A meta-analysis of 25 randomized controlled trials involving individual data on 2596 subjects assessed the effect on plasma homocysteine concentrations of different doses of folic acid and of the addition of vitamins B-12 and B-6. The proportional reductions in plasma homocysteine concentrations produced by folic acid were greater at higher homocysteine (P < 0.001) and lower folate (P < 0.001) pretreatment concentrations; they were also greater in women than in men (P < 0.001). After standardization for sex and to pretreatment plasma concentrations of 12 micromol homocysteine/L and 12 nmol folate/L, daily doses of 0.2, 0.4, 0.8, 2.0, and 5.0 mg folic acid were associated with reductions in homocysteine of 13% (95% CI: 10%, 16%), 20% (17%, 22%), 23% (21%, 26%), 23% (20%, 26%), and 25% (22%, 28%), respectively. Vitamin B-12 (x: 0.4 mg/d) produced 7% (95% CI: 4%, 9%) further reduction in homocysteine concentrations, but vitamin B-6 had no significant effect. Daily doses of > or =0.8 mg folic acid are typically required to achieve the maximal reduction in plasma homocysteine concentrations produced by folic acid supplementation. Doses of 0.2 and 0.4 mg are associated with 60% and 90%, respectively, of this maximal effect.

Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype

Folic acid reduces plasma homocysteine and may be an important therapy for preventing cardiovascular disease. A key mechanism may be the reduction of arterial stiffness. The effect of folic acid supplementation on blood pressure and large artery stiffness was examined in relation to methylenetetrahydrofolate reductase (MTHFR) genotype. Forty-one asymptomatic men with normal or high-normal ambulatory blood pressure (systolic: >130 to <145 mm Hg; diastolic: >80 to <90 mm Hg) participated. The study had a randomized, placebo-controlled, double-blind, crossover design that incorporated 3-wk treatments with 5 mg folic acid/d or matching placebo; each treatment was separated by a 4-wk washout phase. Folic acid reduced brachial pulse pressure by 4.7 +/- 1.6 mm Hg (P < 0.05) without changing mean arterial pressure. Systemic arterial compliance increased by 0.15 +/- 0.03 mL/mm Hg (P < 0.05) after folic acid treatment but did not change after placebo treatment. These responses did not significantly correlate with either homocysteine or folate plasma concentrations. MTHFR genotype CC homozygotes (without the 677C-->T polymorphism) with normal blood pressure had a larger reduction in homocysteine concentrations in response to folic acid than did T allele carriers. Blood pressure and arterial stiffness responses were independent of MTHFR genotype. Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.

Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype

Background: Folic acid reduces plasma homocysteine and may be an important therapy for preventing cardiovascular disease. A key mechanism may be the reduction of arterial stiffness. Objective: The effect of folic acid supplementation on blood pressure and large artery stiffness was examined in relation to methylenetetrahydrofolate reductase (MTHFR) genotype. Design: Forty-one asymptomatic men with normal or high-normal ambulatory blood pressure (systolic: >130 to <145 mm Hg; diastolic: >80 to <90 mm Hg) participated. The study had a randomized, placebo-controlled, double-blind, crossover design that incorporated 3-wk treatments with 5 mg folic acid/d or matching placebo; each treatment was separated by a 4-wk washout phase. Results: Folic acid reduced brachial pulse pressure by 4.7 ± 1.6 mm Hg (P < 0.05) without changing mean arterial pressure. Systemic arterial compliance increased by 0.15 ± 0.03 mL/mm Hg (P < 0.05) after folic acid treatment but did not change after placebo treatment. These responses did not significantly correlate with either homocysteine or folate plasma concentrations. MTHFR genotype CC homozygotes (without the 677C→T polymorphism) with normal blood pressure had a larger reduction in homocysteine concentrations in response to folic acid than did T allele carriers. Blood pressure and arterial stiffness responses were independent of MTHFR genotype. Conclusion: Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.

Homocysteine Lowering by B Vitamins and the Secondary Prevention of Deep-Vein Thrombosis and Pulmonary Embolism. A First Randomised, Placebo-Controlled, Double-Blind Trial.

Hyperhomocysteinemia is a risk factor for venous thrombosis and arterial vascular disease. Supplementation with B-Vitamins (folic acid, vitamin B12 and vitamin B6) reduces homocysteine concentrations by 25–30% in healthy subjects and in patients with venous thrombosis. Until now, there are no results of clinical trials of the effect of homocysteine lowering by B-vitamins on the risk of venous thrombosis.In the VITRO (Vitamins and Thrombosis) study, we investigated the effect of daily supplementation of 5 mg folic acid, 50 mg of pyridoxin and 0.4 mg hydroxycobalamin as secondary prevention of deep-vein thrombosis (DVT) and pulmonary embolism (PE). Patients with primary DVT or PE who were registered for out-patient treatment with an anticoagulation clinic, were asked to participate. Homocysteine was measured and information was retrieved about the diagnosis and circumstances in which patients developed their thrombosis. Patients between 20 to 80 years old with objectively confirmed proximal DVT or PE in the absence of other major risk factors for deep-vein thrombosis (surgery, pregnancy and child-bed, long-term immobility) and a homocysteine concentration in the top quartile entered the study. After informed consent they were randomised to high-dose multivitamin supplementation or placebo and were followed for 2.5 years. End-points were recurrent DVT or PE, as diagnosed by the physician of the patient. Parallel to this study a similar study was conducted in a random sample of patients in the lower three homocysteine quartiles.Subjects were divided according to their homocysteine level in a hyperhomocysteinemic (with a homocysteine concentration in the top quartile, n=360) and a normohomocysteinemic group (a random sample of patients with a homocysteine concentration in the lower three homocysteine quartiles, n=325). The number of recurrent events of thrombosis were 43 out of 348 in the vitamin group (54/1000yr) and 50 out of 353 in the placebo group( 64/1000yr).The relative risk associated with vitamin treatment in the hyperhomocysteinemic group was 1.14 (95%CI 0.65–1.98) and in the normohomocysteinemic group 0.58 (95%CI 0.31–1.07). The overall relative risk was 0.84 (95%CI 0.56–1.26). A baseline homocysteine above the 90th percentile was associated with an increased risk for recurrence of venous thrombosis (RR= 1.9 (95%CI 1.1 tot 3.3). This effect was independent of the treatment regimen. The results of our study does not provide evidence that homocysteine lowering by B-vitamin supplementation prevents recurrent venous thrombosis. The precision of our estimates does not allow to distinguish between ‘no effect' or a 10 to 20% relative risk reduction. However such risk reduction would mean low absolute risk reduction and a number needed to treat of about 50. The fact that baseline homocysteine concentration is a risk factor for recurrence of thrombosis, independent of the treatment, does suggest that other factors - related to homocysteine but not folate - might be involved in the pathogenesis of recurrent thrombosis.

Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C→T mutation on homocysteine concentrations in healthy adults: the ATTICA Study

Dietary and genetic factors may influence the effect of raised homocysteine concentrations on coronary artery disease risk. We evaluated the effect of the interaction between adoption of a Mediterranean diet and the methylenetetrahydrofolate reductase gene (MTHFR) 677C-->T mutation on homocysteine concentrations in healthy adults participating in the ATTICA study. We studied demographic, lifestyle, clinical, biochemical, and genetic information from 322 men (x +/- SD age: 46 +/- 13 y) and 252 women (45 +/- 14 y) who had no clinical evidence of cardiovascular or any other chronic disease. We also measured total plasma homocysteine concentrations, the distribution of the MTHFR genotype, and adherence to a Mediterranean diet. The distribution of MTHFR genotypes was as follows: homozygous normal (CC), 41%; heterozygous (CT), 48%; and homozygous mutant (TT), 11%. Homocysteine concentrations were higher in persons with the TT genotype than in those with the CC and CT genotypes (x +/- SD: 15.8 +/- 9 compared with 11.3 +/- 8 and 10.8 +/- 9 micromol/L, respectively; P < 0.001). The Mediterranean diet score was not significantly associated with homocysteine concentrations (P = 0.89). However, after control for potential confounders, the stratified analysis showed that adherence to a Mediterranean diet was associated with reduced homocysteine concentrations in persons with the TT and CT genotypes (beta = -0.21, P = 0.002, and beta = -0.14, P = 0.025, respectively) but not in those with the CC genotype (beta = -0.03, P = 0.38). The observed association of an MTHFR 677C-->T gene-diet interaction on homocysteine concentrations may provide a pathophysiologic explanation for how a Mediterranean diet may influence coronary risk in persons with raised homocysteine concentrations.

Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial

High homocysteine and low B vitamin concentrations have been linked to the risk of vascular disease, stroke, and dementia and are relatively common in older adults. We assessed the effect of breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 on vitamin and homocysteine status. A randomized, double-blind trial was conducted in 189 volunteers aged 50-85 y. The subjects had no history of hypertension, anemia, asthma, cancer, or cardiovascular or digestive disease and did not regularly consume multiple or B vitamin supplements or highly fortified breakfast cereal. Subjects were randomly assigned to consume 1 cup (0.24 L) breakfast cereal fortified with 440 microg folic acid, 1.8 mg vitamin B-6, and 4.8 microg vitamin B-12 or placebo cereal for 12 wk. Blood was drawn at 0, 2, 12, and 14 wk. Methionine-loading tests were conducted at baseline and week 14. Final baseline-adjusted plasma homocysteine concentrations were significantly lower and B vitamin concentrations were significantly higher in the treatment group than in the placebo group (P < 0.001). The percentage of subjects with plasma folate concentrations < 11 nmol/L decreased from 2% to 0%, with vitamin B-12 concentrations < 185 pmol/L from 9% to 3%, with vitamin B-6 concentrations < 20 nmol/L from 6% to 2%, and with homocysteine concentrations > 10.4 micromol/L (women) or > 11.4 micromol/L (men) from 6.4% to 1.6%. The percentage of control subjects with values beyond these cutoff points remained nearly constant or increased. In this relatively healthy group of volunteers, consumption of 1 cup fortified breakfast cereal daily significantly increased B vitamin and decreased homocysteine concentrations, including post-methionine-load homocysteine concentrations.

Homocysteine and folate: from genes to greens

Several epidemiologic studies have shown correlations between mildly elevated homocysteine levels and cardiovascular disease risk. Hyperhomocysteinemia may be atherogenic or prothrombotic by various mechanisms. Whether mild to moderate hyperhomocysteinemia is a cause, consequence or marker of atherosclerotic vascular disease is still being questioned. The main determinants of plasma homocysteine levels are genetic and nutritional factors. MTHFR 677C>T polymorphism leading to reduced enzyme activity is an important genetic determinant of homocysteine levels. A recent meta-analysis involving more than 23,000 subjects has shown that individuals with the MTHFR 677 TT genotype have 16% higher risk of coronary disease compared with those with the CC genotype. The increase in risk is significant in Europeans but not in North Americans. This discrepancy can be explained by multivitamin intake, ethnic differences and other risk factors showing a typical gene–environment interaction. Folate intake is another determinant of plasma homocysteine levels and dietary supplementation with folic acid, vitamin B12 and B6 can reduce homocysteine concentrations to different extents. However, evidence linking folate and B vitamin levels to cardiovascular disease is inconclusive. Our studies have revealed that patients with the TT genotype and folate levels below the median of the population have the highest homocysteine levels and more extensive atherosclerosis as judged by the coronary angiogram. The important question of whether lowering homocysteine will decrease cardiovascular risk is being addressed by several randomized trials. Meanwhile, two recent trials questioning the effect of lowering homocysteine on restenosis—the Swiss Heart Study and the FACIT trial—have yielded largely discrepant results. Furthermore, a recent trial in patients with stable coronary disease showed that folate supplementation decreased homocysteine levels without having any impact on cardiovascular events. We will have to wait for the results of large randomized trials to see the impact of lowering homocysteine on cardiovascular risk.

Hyperhomocysteinemia and oxidative stress in hemodialysis: effects of supplementation with folic acid.

This study was undertaken to evaluate two different doses of folic acid and their effects on the control of hyperhomocysteinemia, and on pro-oxidant and antioxidant changes in a group of 32 hemodialysis (HD) patients. Blood samples were collected in a group of patients at three different times: before (basal; B), after the first (S1), and after the second (S2) three-month supplementation periods, and compared to samples from a group of healthy individuals. Analysis of vitamins (C, E, folate, and B12), oxidant parameters (lipid and protein oxidation), and homocysteine were performed. Hyperhomocysteinemia of different degrees was observed in all patients on HD (45.30 +/- 24.89 microM). Oxidative stress was also detected, with lipoperoxidation and protein oxidation being associated with lower concentrations of antioxidant substances (vitamins E and C). The first folate dose (2.5 mg after each dialysis session) reduced by half the initial concentrations of homocysteine (44.92 +/- 22.05 to 20.56 +/- 6.79 microM; p < 0.05) but did not normalize its values. The second dose (15 mg) did not show an additional effect, but it was at this time that lipoperoxidation was significantly reduced, although the protein oxidation showed no change. It was concluded that the first dose of folic acid was efficient in reducing homocysteine concentrations, without normalization of values. The participation of hyperhomocysteinemia in oxidative stress appeared to be partial, but in combination with dialysis treatment, may contribute to the induction of an oxidative environment in this group. The possible antioxidant action of folate must also be considered in this case, acting directly against lipoperoxidation or through hyperhomocysteinemia control. Routine supplementations of folic acid and other antioxidant vitamins should be considered in hemodialysis in order to reduce homocysteine levels to lower values, that although not normal, may be more beneficial in minimizing the cardiovascular risk in this group.

Effects of 3-deazaadenosine on homocysteine and atherosclerosis in apolipoprotein E-deficient mice

Objective: In the past decade, elevated homocysteine concentration has achieved widespread recognition as an independent risk factor in the development of atherosclerosis. 3-Deazaadenosine (c 3Ado) is a potent inhibitor and substrate for S-adenosylhomocysteine hydrolase and therefore may reduce homocysteine concentrations. The current study investigated the effect of c 3Ado on serum homocysteine, atherosclerotic lesions, and the expression of adhesion molecules in apoE-knockout mice. Methods and results: Animals were placed on an atherogenic diet with or without c 3Ado for 12 and 24 weeks. Frozen cross-sections of the aortic sinus and the proximal aorta were analyzed by computer-aided planimetry for fatty plaque formation. Macrophages, VCAM-1 and ICAM-1 were quantified by immunhistochemistry and oligo-cell reverse transcription polymerase chain reaction after laser microdissection. Application of c 3Ado resulted in significant reduction of homocysteine levels by 35.9 and 45.3% after 12 and 24 weeks, respectively ( P<0.001). Neointimal area and atherosclerotic plaque formation were significantly reduced in animals treated with c 3Ado ( P<0.01). Moreover, monocyte adhesion and concomitant ICAM-1 and VCAM-1 antigen and RNA expression on the endothelial layer were significantly reduced ( P<0.001, P<0.01). Conclusion: Our results demonstrate that c 3Ado induces a marked reduction of homocysteine concentrations which might explain in part the anti-atherogenic effect of the drug.