5-Methyltetrahydrofolate Rapidly Improves Endothelial Function and Decreases Superoxide Production in Human Vessels: Effects on Vascular Tetrahydrobiopterin Availability and Endothelial Nitric Oxide Synthase Coupling
Abstract
Background— The circulating form of folic acid, 5-methyltetrahydrofolate (5-MTHF), may have beneficial effects on endothelial function; however, its mechanisms of action remain uncertain. Decreased nitric oxide (NO) bioavailability and increased vascular superoxide production in vascular disease states are due in part to endothelial NO synthase (eNOS) uncoupling related to deficiency of the eNOS cofactor tetrahydrobiopterin (BH 4 ), but whether this mechanism is important in human atherosclerosis and represents a rational therapeutic target remains unclear. We hypothesized that 5-MTHF would improve endothelial function by decreasing superoxide and peroxynitrite production and by improving eNOS coupling, mediated by BH 4 availability. Methods and Results— Vascular superoxide/peroxynitrite production and vasomotor responses to acetylcholine and bradykinin were determined in saphenous veins and internal mammary arteries from 117 patients undergoing CABG. The effects of 5-MTHF were examined ex vivo (n=61) by incubating vessels with 5-MTHF (1 to 100 μmol/L) and in vivo by intravenous infusion of 5-MTHF or placebo before vessel harvest (n=56). 5-MTHF improved NO-mediated endothelium-dependent vasomotor responses and reduced vascular superoxide, both ex vivo and in vivo. These changes were not explained by direct superoxide scavenging by 5-MTHF in vitro or by changes in plasma total homocysteine in vivo. Rather, 5-MTHF was a strong peroxynitrite scavenger and increased vascular BH 4 and the BH 4 /total biopterin ratio. Furthermore, 5-MTHF reversed eNOS uncoupling, as assessed by N G -nitro- l -arginine methyl ester–inhibitable superoxide production, increased the eNOS dimer:monomer ratio, and enhanced eNOS activity. Conclusions— 5-MTHF has beneficial effects on endothelial function and vascular superoxide production in human atherosclerosis, by preventing peroxynitrite-mediated BH 4 oxidation and improving eNOS coupling.
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Related pterins, such as folate, can produce effects similar to BH4.
“related pterins, such as folate, can also produce similar effects (32, 33, 860).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [33]
Folic acid supplementation in human blood vessel samples increases BH4 levels and BH4/BH2 ratios.
“Folic acid supplementation studies in human blood vessel samples have shown increases in BH4 levels and BH4/BH2 ratios (33).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [33]
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- Authors
- Antoniades, C., Shirodaria, C., Warrick, N., Cai, S., de Bono, J., Lee, J., Leeson, P., Neubauer, S., Ratnatunga, C., Pillai, R., Refsum, H., & Channon, K. M.
- Affiliations
- John Radcliffe Hospital (GB)
- From the Departments of Cardiovascular Medicine and Cardiac Surgery (C.A., C.S., N.W., S.C., J.d.B., J.L., P.L., S.N., C.R., R.P., K.M.C.), John Radcliffe Hospital, and Oxford Centre for Gene Function (H.R.), University Laboratory of Physiology, University of Oxford, Oxford, United Kingdom.
- ORCID
- Venue
- Circulation
- Published
- 2006-09-12
- Volume
- 114
- Issue
- 11
- Pages
- 1193-1201
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2117238388
- Cited by
- 365
- References
- 33
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 15 · 2023: 14 · 2022: 9 · 2021: 6 · 2020: 21 · 2019: 17 · 2018: 19 · 2017: 22 · 2016: 13 · 2015: 17 · 2014: 26 · 2013: 21 · 2012: 27
- FWCI
- 15.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Merck KGaA
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- 5-methyltetrahydrofolate, endothelial function, superoxide production, peroxynitrite, tetrahydrobiopterin, eNOS uncoupling, nitric oxide bioavailability, atherosclerosis, homocysteine, saphenous vein, internal mammary artery
- MeSH terms
- Acetylcholine, Antioxidants, Coronary Artery Bypass, Biological Availability, Biopterins, Bradykinin, Coronary Artery Disease, Double-Blind Method, Endothelium, Vascular, Homocysteine, Humans, Nitric Oxide, Protein Binding, Superoxides, Tetrahydrofolates, Peroxynitrous Acid, Atherosclerosis, Nitric Oxide Synthase Type III
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