ArticleThe Journal of biological chemistry2009
Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
113 citing papers in PubMed, 208 citations in OpenAlex.
- Trial
- Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease.Circulation · 2012Trial
- Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women.American journal of physiology. Heart and circulatory physiology · 2012Trial
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- Ferroptosis and Ferroptosis-related autophagy: new therapeutic targets for gastric cancer.American journal of cancer research · 2026Review
- Neuroferroptosis in health and diseases.Nature reviews. Neuroscience · 2025Review
- Ferroptosis: a potential target for non-surgical treatment of laryngeal cancer.European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2025Review
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- Promotion of nitric oxide production: mechanisms, strategies, and possibilities.Frontiers in physiology · 2025Review
- Nitric Oxide in Biomaterial-Based Therapies for Coronary Heart Disease: Mechanistic Insights, Current Advances, and Translational Prospects.Biomaterials research · 2025Review
- Ferroptosis and its Potential Determinant Role in Myocardial Susceptibility to Ischemia/Reperfusion Injury in Diabetes.Reviews in cardiovascular medicine · 2024Review
- Article
- Cinnamaldehyde Protects againstInternational journal of molecular sciences · 2024Article
- Association Between Serine Concentration and Coronary Heart Disease: A Case-Control Study.International journal of general medicine · 2024Article
- Cardiomyocyte tetrahydrobiopterin synthesis regulates fatty acid metabolism and susceptibility to ischaemia-reperfusion injury.Experimental physiology · 2023Article
- Endothelial cell-specific roles for tetrahydrobiopterin in myocardial function, cardiac hypertrophy, and response to myocardial ischemia-reperfusion injury.American journal of physiology. Heart and circulatory physiology · 2023Article
- Associations of Biopterins and ADMA with Vascular Function in Peripheral Microcirculation from Patients with Chronic Kidney Disease.International journal of molecular sciences · 2023Article
- Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets.Cellular & molecular biology letters · 2023Article
53 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
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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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.