5-Methyltetrahydrofolate Rapidly Improves Endothelial Function and Decreases Superoxide Production in Human Vessels

Antoniades, Charalambos; Shirodaria, C; Warrick, N; Cai, Shijie; Bono, Joseph de; Lee, Justin; Leeson, Paul; Neubauer, Stefan; Ratnatunga, C; Pillai, Ravi; Refsum, Helga; Channon, Keith M.

doi:10.1161/circulationaha.106.612325

Cited by 325 publications

(195 citation statements)

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“…However, venous and arterial ECs are exposed to the same circulating pro‐inflammatory factors in inadequate sleep. Inflammatory and oxidative pathways are activated similarly in venous and arterial ECs in healthy subjects and patients with atherosclerosis 44, 45. Furthermore, the cell culturing process rapidly erases arteriovenous gene expression differences that are present in freshly isolated ECs 46.…”

Section: Discussionmentioning

confidence: 99%

Effects of Inadequate Sleep on Blood Pressure and Endothelial Inflammation in Women: Findings From the American Heart Association Go Red for Women Strategically Focused Research Network

Aggarwal

Makarem

Shah

et al. 2018

JAHA

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BackgroundInsufficient sleep increases blood pressure. However, the effects of milder, highly prevalent but frequently neglected sleep disturbances, including poor sleep quality and insomnia, on vascular health in women are unclear. We investigated whether poor sleep patterns are associated with blood pressure and endothelial inflammation in a diverse sample of women.Methods and ResultsWomen who participated in the ongoing American Heart Association Go Red for Women Strategically Focused Research Network were studied (n=323, 57% minority, mean age=39±17 years, range=20–79 years). Sleep duration, sleep quality, and time to sleep onset were assessed using the Pittsburgh Sleep Quality Index (score ≥5=poor sleep quality). Risk for obstructive sleep apnea was evaluated using the Berlin questionnaire, and insomnia was assessed using the Insomnia Severity Index. In a subset of women who participated in the basic study (n=26), sleep duration was assessed objectively using actigraphy, and endothelial inflammation was assessed directly in harvested endothelial cells by measuring nuclear translocation of nuclear factor kappa B. Vascular reactivity was measured by brachial artery flow‐mediated dilation (n=26). Systolic and diastolic blood pressure were measured by trained personnel (n=323). Multivariable linear regressions were used to evaluate associations between sleep patterns and blood pressure, nuclear factor kappa B, and flow‐mediated dilation. Mean sleep duration was 6.8±1.3 hours/night in the population study and 7.5±1.1 hour/night in the basic study. In the population study sample, 50% had poor sleep quality versus 23% in the basic study, and 37% had some level of insomnia versus 15% in the basic study. Systolic blood pressure was associated directly with poor sleep quality, and diastolic blood pressure was of borderline significance with obstructive sleep apnea risk after adjusting for confounders (P=0.04 and P=0.08, respectively). Poor sleep quality was associated with endothelial nuclear factor kappa B activation (β=30.6; P=0.03). Insomnia and longer sleep onset latency were also associated with endothelial nuclear factor kappa B activation (β=27.6; P=0.002 and β=8.26; P=0.02, respectively). No evidence was found for an association between sleep and flow‐mediated dilation.ConclusionsThese findings provide direct evidence that common but frequently neglected sleep disturbances such as poor sleep quality and insomnia are associated with increased blood pressure and vascular inflammation even in the absence of inadequate sleep duration in women.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02835261.

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Section: Discussionmentioning

confidence: 99%

Effects of Inadequate Sleep on Blood Pressure and Endothelial Inflammation in Women: Findings From the American Heart Association Go Red for Women Strategically Focused Research Network

Aggarwal

Makarem

Shah

et al. 2018

JAHA

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“…First, folic acid or vitamin supplementation significantly reduces carotid intima-media thickness in patients with heart disease (38,39) , a history of stroke or at risk for cerebral ischaemia (40,41) ; an increased carotid intima-media thickness serves as a predictor of coronary and cerebrovascular complications (42) . Second, the antioxidant capacities of folic acid and its metabolite 5-methyltetrahydrofolate or the antioxidants from multivitamins may reduce oxidative stress and superoxide production (43)(44)(45) . Moreover, a high-dose folic acid or vitamin therapy can lower blood pressure, enhance coronary dilation in patients with coronary artery disease (46) and improve endothelial function in patients with metabolic syndrome, CHD or diabetes (43,45,(47)(48)(49) ; these improvements are independent of homocysteine lowering.…”

Section: Discussionmentioning

confidence: 99%

“…Second, the antioxidant capacities of folic acid and its metabolite 5-methyltetrahydrofolate or the antioxidants from multivitamins may reduce oxidative stress and superoxide production (43)(44)(45) . Moreover, a high-dose folic acid or vitamin therapy can lower blood pressure, enhance coronary dilation in patients with coronary artery disease (46) and improve endothelial function in patients with metabolic syndrome, CHD or diabetes (43,45,(47)(48)(49) ; these improvements are independent of homocysteine lowering. In addition, the use of multivitamins reduces C-reactive protein levels, a risk factor for CVD (50) .…”

Section: Discussionmentioning

confidence: 99%

The prevalence and correlates of taking folic acid and vitamin supplements among adults aged ≥45 years with CVD

Zhao

Ford

et al. 2010

Public Health Nutr.

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Objective: To examine the prevalence and likelihood of taking folic acid or vitamin supplements among adults with CHD or stroke v. adults without these conditions. Design: A cross-sectional Behavioural Risk Factor Surveillance System survey was conducted in twelve states of the United States and Puerto Rico in 2006. Selfreported data from participants were collected. Setting: The United States. Subjects: US non-institutionalised adults (n 41 792), aged $45 years. Results: Of all participants, 5445 had CHD and 2076 had stroke. Significantly higher percentages of women than men reported taking folic acid or vitamin supplements. After adjustment for potential confounders, women with CHD had a significantly lower adjusted prevalence (AP) and adjusted OR (AOR) than women without CHD for taking folic acid less than one time per d (AP 5 3?9 % v. Keywords Folic acid Vitamins Coronary heart disease StrokeAlthough the mortality rate of patients with CHD has decreased by 52 % in men and 49 % in women from 1980 to 2002 (1) and the mortality rate of stroke decreased by 24?2 % from 1994 to 2004 (2) , the burden of these diseases remains high. Among US adults, the prevalence of CHD was 7?3 % and the prevalence of stroke was 2?6 % in 2005. Hyperhomocysteinaemia is associated with an increased risk for CVD (3)(4)(5) . Results from meta-analyses have shown that for a 5 mmol/l increase in serum homocysteine levels, the risk of myocardial infarction increased by 84 % (5) , the risk of CHD increased by 23-70 % (4) , and the risk of cerebrovascular disease increased by 58-116 % (4) , although prospective studies offer weaker support for this association than case-control studies (4) . A higher intake of folic acid or multivitamins reduces serum homocysteine levels (6,7) and is associated with reduced risk of acute coronary events and myocardial infarction (8)(9)(10)(11) or reduced rates of coronary restenosis and revascularisation in patients with coronary angioplasty (12,13) . However, other studies including recent clinical trials failed to show any beneficial effects on the risk of recurrent CVD or on total CVD or CHD mortality when using folic acid and B vitamins to lower homocyteine levels among patients with pre-existing CVD or renal disease (14)(15)(16)(17) or among people at high risk for CVD (having a history of vascular disease, diabetes or other coronary risk factors) (18,19) .

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“…Nitroxidative stress is indeed increased in COPD, and inhibition of inducible nitric oxide synthase protects mice from smoke-induced emphysema and pulmonary hypertension [87][88][89][90]. When folic acid is administered in supraphysiologic doses, high intracellular concentrations of tetrahydrofolates accumulate in most cells, and can exert potent oxidant scavenging effects most notably, scavenging of peroxynitrite -derived radicals [91,92]. This may explain high dose folate's ability to recouple endothelial nitric oxide synthase in patients with endothelial dysfunction, and to provide marked protection from cardiac ischemia reperfusion damage [93][94][95][96][97][98][99].…”

Section: Adjuvant Strategies Targeting Nrf2mentioning

confidence: 99%

DHA May Have a Profoundly Protective Impact on the Lungs of Smokers

Mf¹

2016

J Nutr Food Sci

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Evidence has accumulated over the last twenty years that smokers who frequently ingest fish are at lower risk for both chronic obstructive pulmonary disease (COPD) and lung cancer. Plasma phospholipid levels of DHA, but not EPA, have been reported to correlate inversely with risk for COPD in smokers, suggesting that DHA may be primarily responsible for the apparent protection afforded to lungs of smokers by fish consumption. Meanwhile, evidence is emerging that certain metabolites of DHA -including 4 -hydroxy hexenal (4-HHE), 17 -oxo -DHA, and resolvin D1 -can activate Nrf2 -mediated transcription of heme oxygenase -1 and other antioxidant / cytoprotective enzymes. Since the oxidant stress imposed by cigarette smoke exposure could be expected to promote peroxidation of membrane DHA and hence boost production of 4 -HHE, DHA in lung membranes may in effect up-regulate the protective feedback mechanism whereby oxidative stress provokes Nrf2 -mediated induction of cytoprotective enzymes. DHA can also give rise to the autacoid resolvin D1, which, via activation of a receptor, suppresses NFkappaB activation and the consequent production of pro-inflammatory cytokines. Resolvin D1 can also inhibit macrophage NADPH oxidase and promote an anti-inflammatory M2 phenotype in lung macrophages. Not surprisingly, inhalation of resolvin D1 has a marked anti-inflammatory impact on the lungs of mice exposed to tobacco smoke. These considerations help to rationalize the epidemiology linking fish consumption to lung health, and suggest that smokers who can't or won't quit their habit would be well advised to consume fish or DHA supplements regularly. Higher intakes of fruits and vegetables -likely in part because many of these contain Nrf2 -activating phytochemicals -likewise are associated with lower risk for COPD, and can be recommended for smokers.Keywords: COPD; Lung cancer; Fish; Docosahexaenoic acid (DHA); 4 -hydroxy hexenal; Nrf2; Resolvin D1 Fish Consumption May Protect Smokers from COPDLimited but nonetheless compelling epidemiology has linked heavy dietary consumption of fresh fish to marked decreases in risk for lung cancer and chronic obstructive pulmonary disease (COPD) among smokers. The first key evidence in this regard emerged in 1994. Shahar et al.[1] studied subjects enrolled in the prospective Atherosclerosis Risk in Communities (ARIC) study, who had received a dietary assessment and a physical exam including lung spirometry, and had been questioned regarding lung symptoms [1]. COPD was defined by three separate criteria: self -reported symptoms of chronic bronchitis, physician diagnosis of emphysema, and via spirometry (FEV1 < 65% of predicted value). When risk for COPD was compared between the first and fourth quartiles of estimated daily intake of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), relative risk for COPD in the fourth quartile (mean omega-3 intake 480 mg) after appropriate multivariate adjustments was found to be 0.66 (95% CI 0.52 -0.85), 0.31 (CI 0.18 -0.52), and 0.50 (CI 0.32...

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5-Methyltetrahydrofolate Rapidly Improves Endothelial Function and Decreases Superoxide Production in Human Vessels

Abstract: 5-MTHF has beneficial effects on endothelial function and vascular superoxide production in human atherosclerosis, by preventing peroxynitrite-mediated BH4 oxidation and improving eNOS coupling.

Cited by 325 publications

References 32 publications

Effects of Inadequate Sleep on Blood Pressure and Endothelial Inflammation in Women: Findings From the American Heart Association Go Red for Women Strategically Focused Research Network

Effects of Inadequate Sleep on Blood Pressure and Endothelial Inflammation in Women: Findings From the American Heart Association Go Red for Women Strategically Focused Research Network

The prevalence and correlates of taking folic acid and vitamin supplements among adults aged ≥45 years with CVD

DHA May Have a Profoundly Protective Impact on the Lungs of Smokers

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