Critical Role for Tetrahydrobiopterin Recycling by Dihydrofolate Reductase in Regulation of Endothelial Nitric-oxide Synthase Coupling
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Tetrahyrobiopterin (BH4) is a required cofactor for the synthesis of nitric oxide by endothelial nitric-oxide synthase (eNOS), and BH4 bioavailability within the endothelium is a critical factor in regulating the balance between NO and superoxide production by eNOS (eNOS coupling). BH4 levels are determined by the activity of GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in de novo BH4 biosynthesis. However, BH4 levels may also be influenced by oxidation, forming 7,8-dihydrobiopterin (BH2), which promotes eNOS uncoupling. Conversely, dihydrofolate reductase (DHFR) can regenerate BH4 from BH2, but the functional importance of DHFR in maintaining eNOS coupling remains unclear. We investigated the role of DHFR in regulating BH4 versus BH2 levels in endothelial cells and in cell lines expressing eNOS combined with tet-regulated GTPCH expression in order to compare the effects of low or high levels of de novo BH4 biosynthesis. Pharmacological inhibition of DHFR activity by methotrexate or genetic knockdown of DHFR protein by RNA interference reduced intracellular BH4 and increased BH2 levels resulting in enzymatic uncoupling of eNOS, as indicated by increased eNOS-dependent superoxide but reduced NO production. In contrast to the decreased BH4:BH2 ratio induced by DHFR knockdown, GTPCH knockdown greatly reduced total biopterin levels but with no change in BH4:BH2 ratio. In cells expressing eNOS with low biopterin levels, DHFR inhibition or knockdown further diminished the BH4:BH2 ratio and exacerbated eNOS uncoupling. Taken together, these data reveal a key role for DHFR in eNOS coupling by maintaining the BH4:BH2 ratio, particularly in conditions of low total biopterin availability.
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The BH4/BH2 ratio gives a more precise estimation of endothelial function than the relative amount of BH2.
“Thus, rather than the relative amount of BH2, the BH4/BH2 ratio gives a more precise estimation of the endothelial function (190, 192, 974).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [192]
The conversion of BH4 to BH2 in the setting of endothelial dysfunction has been widely reported.
“The conversion of BH4 to BH2 in the setting of endothelial dysfunction has been widely reported (192, 258, 550).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [192]
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- Authors
- Crabtree, M. J., Tatham, A. L., Hale, A. B., Alp, N. J., & Channon, K. M.
- Affiliations
- John Radcliffe Hospital (GB)
- Corresponding author
- Channon, Keith M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 284
- Issue
- 41
- Pages
- 28128-28136
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2788863
- OpenAlex
- W2058599067
- Cited by
- 210
- References
- 36
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 11 · 2023: 13 · 2022: 13 · 2021: 12 · 2020: 14 · 2019: 13 · 2018: 12 · 2017: 17 · 2016: 11 · 2015: 12 · 2014: 13 · 2013: 6 · 2012: 12
- FWCI
- 11.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (GR074428/Z/04/Z)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- tetrahydrobiopterin, dihydrofolate reductase, endothelial nitric oxide synthase, eNOS uncoupling, 7,8-dihydrobiopterin, GTP cyclohydrolase I, nitric oxide production, superoxide production, methotrexate, endothelial cells
- MeSH terms
- Animals, Antioxidants, Biopterins, Cell Line, Cells, Cultured, Doxycycline, Endothelium, Vascular, GTP Cyclohydrolase, Methotrexate, Oxidation-Reduction, Superoxides, Tetrahydrofolate Dehydrogenase, RNA, Small Interfering, NIH 3T3 Cells, Endothelial Cells, Mice, Nitric Oxide Synthase Type III
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