Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease

Title, Lawrence M.; Cummings, Peter M.; Giddens, Karen; Genest, J; Nassar, B.A.

doi:10.1016/s1062-1458(00)00174-4

Cited by 23 publications

(36 citation statements)

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“…For example, 5‐methyltetrahydrofolate, an active metabolite of folate, acts to stabilize and regenerate production of tetrahydrobiopterin (Verhaar et al ., ; Miller, ), which is an essential cofactor for eNOS. It can rescue endothelial cells with homocysteine‐mediated injury and can increase eNOS activity (Stroes et al ., ; Title et al ., ; Sasaki et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Molecular mechanisms underlying the anti‐proliferative and anti‐migratory effects of folate on homocysteine‐challenged rat aortic smooth muscle cells

Chou

Lin

Chen

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEHomocysteine is an intermediate product formed during the metabolism of methionine, and is increased in cells with folate deficiency. Patients with hyperhomocysteinemia tend to develop cardiovascular disease. Here, we have examined the molecular mechanisms underlying the anti-proliferative and anti-migratory effects of folate on homocysteine-challenged rat aortic smooth muscle cells (RASMCs). EXPERIMENTAL APPROACHCultures of RASMC were challenged with homocysteine and then incubated with folate added. Changes in p21/p27, AKT and RhoA were followed by RT-PCR, Western blotting and immunocytochemistry. Transfection and anti-sense techniques were also used. Cell viability, growth and migration were measured. KEY RESULTSFolate up-regulated p21/p27 through a Src/ERK-dependent mechanism that accounted for its anti-proliferative effects on RASMC. Folate protected RASMC from the effects of homocysteine by reducing AKT1, focal adhesion kinase (FAK), paxillin, and p190RhoGAP activation/phosphorylation, along with cytosolic levels of p21 and p27, and increasing RhoA activation. Overexpression of AKT1, but not of AKT2, induced p21/p27 phosphorylation and increased cytosolic p21/p27 levels, as did homocysteine treatment. By contrast, and similarly to folate treatment, transfection with dominant negative (DN) AKT1 counteracted these effects. Additionally, AKT was shown to be an upstream target of FAK activation. In RASMC overexpressing constitutively active RhoA, activation of RhoA mediated the anti-migratory effects of folate. Addition of Y27632 (a RhoA inhibitor) and DNRhoA counteracted the anti-migratory effects, confirming RhoA involvement. CONCLUSION AND IMPLICATIONSFolate was anti-proliferative and anti-migratory in homocysteine-challenged RASMC. Mechanisms underlying folate-mediated protection against the proatherosclerotic effects of homocysteine have been delineated. AbbreviationsASp21, antisense p21; ASp27, antisense p27; CARhoA, constitutive active RhoA; DNRhoA, dominant negative RhoA; FAK, focal adhesion kinase; PP2, 4-amino-5-(4-chloro-phenyl)-7-(t-butyl) pyrazolo [3,4-d]pyrimidine; RASMC, rat aortic smooth muscle cell BJP British Journal of Pharmacology

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Section: Introductionmentioning

confidence: 97%

Molecular mechanisms underlying the anti‐proliferative and anti‐migratory effects of folate on homocysteine‐challenged rat aortic smooth muscle cells

Chou

Lin

Chen

et al. 2013

British J Pharmacology

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“…Previous studies among CAD patients have shown that folate supplementations at doses ranging from 0.127-10 mg/day were associated with homocysteine levels that were reduced by 3.7% to 34%, with varying degrees of reduction for individual doses. (29)(30)(31)(32) The Homocysteine Lowering Trialists' meta-analysis examined the effect of folate supplementation on plasma homocysteine levels among 1,114 subjects across 12 trials, and showed that dietary folic acid reduced blood homocysteine concentrations by 25%, with similar effects of folate supplementation in the range of 0.5-5 mg daily. (33) The results of the present study fall midway between the higher percentages of reduction seen in this metaanalysis (33) and the lower percentages of reduction seen in patients with CAD.…”

Section: Discussionmentioning

confidence: 99%

“…(4,41) On the other hand, a recent systematic review and meta-analysis of 16 randomized controlled trials found no effect of vitamin D on endothelial function, (42) and two large-scale trials could not find any association between vitamin C and E supplements and major cardiovascular outcomes. (43,44) Title et al (30) found that a supplement containing folic acid and other antioxidants (vitamin C and E) did not significantly improve endothelial function, whereas a supplement containing folate alone did, despite the beneficial effects of combined therapy on lipid peroxidation. Some unfavourable interactions between vitamins C, E, and folate might modify the effects of vitamin B supplementation.…”

Section: Discussionmentioning

confidence: 99%

Association between vitamin B group supplementation with changes in % flow-mediated dilatation and plasma homocysteine levels: a randomized controlled trial

Maruyama

Eshak

Kinuta

et al. 2019

J. Clin. Biochem. Nutr.

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There is limited evidence examining the association between B vitamin supplementation and improved endothelial function via lowering plasma homocysteine levels. This study investigated whether low dose B vitamin supplementation improves endo thelial dysfunction in Japanese adults with one or more compo nents of metabolic syndrome. A randomized, controlled, crossover trial, without a washout period or blinding of subjects, was conducted from May September, 2010. The subjects were 127 Japanese men and women aged 40-65 years who had at least one component of metabolic syndrome without medication. Participants took a supplement drink for two months but were divided into early intervention or later intervention groups. The flow mediated dilatation, plasma homocysteine level, serum B vitamins, and vitamin C levels were measured. A significant increase in serum B vitamins and vitamin C levels, and a reduction in plasma homocysteine levels were observed. The mean serum homocysteine level pre and post intervention was 9.8 and 8.2 µmol/L in the early intervention group and 10.8 and 7.4 µmol/L in the later intervention group (p<0.01). However, no significant changes in flow mediated dilatation was found. Low dose multi vitamin supplementation including B vitamins is associated with a significant reduction in plasma homocysteine levels among patients with one or more components of metabolic syndrome. This study was registered at the University Hospital Medical Information Network (UMIN) centre, and has the identifier UMIN000004436.

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“…47 It is well established that FA lowers plasma HCY concentration, 48 and at the same time, it improves endothelial function. 43,49 Furthermore, FA also improves endothelial function independently from its HCY-lowering effect. 45,50 Vitamin B 6 is a powerful antioxidant vitamin that can prevent low-density lipoprotein-induced impairment of endothelial cell NO generation.…”

Section: B Vitamins In Cardiovascular Healthmentioning

confidence: 98%

Role of vitamins in cardiovascular health and disease

Debreceni¹,

Debreceni²

2014

RRCC

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Cardiovascular disease (CVD) is the leading cause of mortality around the world. The prevention of CVD is a main goal of health care. Vitamins, especially those with antioxidant potency, may have a role in the prevention of and therapy for CVD. Antioxidant vitamins, vitamin C, vitamin E, and carotenoids are able to decrease the rate of oxidative stress, which may have a principal role in the pathogenesis of atherosclerosis and CVD. Vitamin B 6 , vitamin B 12 , and folic acid, as well as vitamin D, also contribute to maintenance of cardiovascular health and can induce cardioprotective effects. Although most of the randomized controlled trials on vitamins failed to show the benefit of vitamin supplementation for cardiovascular outcomes, a number of observational and cohort studies, meta-analyses, and stratified analyses of large vitamin trials appeared to show an effect in some aspects of cardiovascular prevention. Moreover, many of the vitamin trials for secondary prevention are biased by use of vitamins and drugs effective for cardiovascular prevention; therefore, the conclusions drawn from them supporting the effectiveness of vitamin substitution for the prevention of CVD may be inappropriate. To summarize, there are abundant data suggesting the role of vitamins in cardiovascular health and in the primary prevention of CVD; however, examinations using new concepts and new study designs are needed to establish the effectiveness of vitamin supplementation in the therapy for and prevention of CVD.

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Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease

Cited by 23 publications

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Molecular mechanisms underlying the anti‐proliferative and anti‐migratory effects of folate on homocysteine‐challenged rat aortic smooth muscle cells

Molecular mechanisms underlying the anti‐proliferative and anti‐migratory effects of folate on homocysteine‐challenged rat aortic smooth muscle cells

Association between vitamin B group supplementation with changes in % flow-mediated dilatation and plasma homocysteine levels: a randomized controlled trial

Role of vitamins in cardiovascular health and disease

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