Folic Acid Reverts Dysfunction of Endothelial Nitric Oxide Synthase
Abstract
Abstract —5-Methyltetrahydrofolate (MTHF), the active form of folic acid, has been reported to restore NO status in hypercholesterolemic patients. The mechanism of this effect remains to be established. We assessed the effects of L- and D-MTHF on tetrahydrobiopterin (BH 4 )–free and partially BH 4 -repleted endothelial NO synthase (eNOS). Superoxide production of eNOS and the rate constants for trapping of superoxide by MTHF were determined with electron paramagnetic resonance using 5-diethoxyphosphoryl-5-methyl-1-pyrroline- N -oxide (DEPMPO) as spin trap for superoxide. NO production was measured with [ 3 H]arginine–citrulline conversion or nitrite assay. The rate constants for scavenging of superoxide by L- and D-MTHF were similar, 1.4×10 4 ms –1 . In BH 4 -free eNOS, L- and D-MTHF have no effect on enzymatic activity. In contrast, in partially BH 4 -repleted eNOS, we observe a 2-fold effect of MTHF on the enzymatic activity. First, superoxide production is reduced. Second, NO production is enhanced. In cultured endothelial cells, a similar enhancement of NO production is induced by MTHF. In the present study, we show direct effects of MTHF on the enzymatic activity of NO synthase both in recombinant eNOS as well as in cultured endothelial cells, which provides a plausible explanation for the previously reported positive effects of MTHF on NO status in vivo.
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Supplementation with vitamin B12, B6, and folic acid resulted in the reduction of homocysteine and oxidative stress.
“Supplementation with vitamin B12, B6, and folic acid resulted in the reduction of homocysteine and oxidative stress (Stroes et al. 2000).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Stroes et al. 2000
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- Authors
- Stroes, E. S. G., van Faassen, E. E., Yo, M., Martasek, P., Boer, P., Govers, R., & Rabelink, T. J.
- Affiliations
- Utrecht University (NL)
- From the Departments of Vascular Medicine (E.S.G.S., M.Y., R.G., T.J.R.) and Nephrology (P.B.), University Hospital Utrecht, The Netherlands; Debye Institute (E.E.v.F.), University Utrecht, The Netherlands; and Department of Pediatrics, First Faculty of Medicine (P.M.), Charles University, Prague, Czech Republic.
- Venue
- Circulation Research
- Published
- 2000-06-09
- Volume
- 86
- Issue
- 11
- Pages
- 1129-1134
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2097980836
- Cited by
- 285
- References
- 47
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 10 · 2016: 5 · 2015: 10 · 2014: 13 · 2013: 5 · 2012: 7
- FWCI
- 9.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- 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
- folic acid, 5-methyltetrahydrofolate, endothelial nitric oxide synthase, tetrahydrobiopterin, superoxide production, nitric oxide production, superoxide radical scavenging, endothelial dysfunction, hypercholesterolemia, endothelial cells
- MeSH terms
- Cells, Cultured, Electron Spin Resonance Spectroscopy, Endothelium, Vascular, Nitric Oxide, Pterins, Recombinant Proteins, Superoxides, Tetrahydrofolates, Xanthine Oxidase, Nitric Oxide Synthase, Nitric Oxide Synthase Type III
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