ArticleFree radical biology & medicine2011
Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency.
Article in Free radical biology & medicine, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 134 citations in OpenAlex.
- Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease.Circulation · 2012Trial
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- The role of gasotransmitters in Parkinson's disease: Interplay of nitric oxide, carbon monoxide, and hydrogen sulfide.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 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
- Butyrate Produced by Gut Microbiota Regulates Atherosclerosis: A Narrative Review of the Latest Findings.International journal of molecular sciences · 2025Review
- Evaluation of kidney injury and metabolomic analysis in adulthood in a non-obese hyperglycemic female mouse model after birth with low birthweight.BMC nephrology · 2025Article
- Promotion of nitric oxide production: mechanisms, strategies, and possibilities.Frontiers in physiology · 2025Review
- Declining nitric oxide bioavailability in cardiovascular aging: mechanistic insights and emerging interventions.The journal of cardiovascular aging · 2025Article
- NO/NOS system dysregulation as a key molecular mechanism in chemotherapy-induced cardiotoxicity: a review.Frontiers in cardiovascular medicine · 2025Review
- The Significance of Genetically Determined Methylation and Folate Metabolism Disorders in the Pathogenesis of Coronary Artery Disease: A Target for New Therapies?International journal of molecular sciences · 2024Review
- Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.British journal of cancer · 2024Article
- Role of Oxidative Stress in Sensorineural Hearing Loss.International journal of molecular sciences · 2024Review
- Si-based agent alleviated small bowel ischemia-reperfusion injury through antioxidant effects.Scientific reports · 2024Article
- Coronary Artery Disease Is Related to Methylation Disorders Caused by the c.1286A>CReports (MDPI) · 2024Article
- Lymphocyte-Specific Protein 1 Regulates Expression and Stability of Endothelial Nitric Oxide Synthase.Biomolecules · 2024Article
- Tryptophan Metabolism in Obesity: The Indoleamine 2,3-Dioxygenase-1 Activity and Therapeutic Options.Advances in experimental medicine and biology · 2024Review
6 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Tetrahydrobiopterin (BH4) is a required cofactor for the synthesis of NO by endothelial nitric oxide synthase (eNOS), and endothelial BH4 bioavailability is a critical factor in regulating the balance between NO and superoxide production (eNOS coupling). Biosynthesis of BH4 is determined by the activity of GTP-cyclohydrolase I (GTPCH). 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 whether DHFR is functionally important in maintaining eNOS coupling remains unclear. To investigate the mechanism by which DHFR might regulate eNOS coupling in vivo, we treated wild-type, BH4-deficient (hph-1), and GTPCH-overexpressing (GCH-Tg) mice with methotrexate (MTX), to inhibit BH4 recycling by DHFR. MTX treatment resulted in a striking elevation in BH2 and a decreased BH4:BH2 ratio in the aortas of wild-type mice. These effects were magnified in hph-1 but diminished in GCH-Tg mice. Attenuated eNOS activity was observed in MTX-treated hph-1 but not wild-type or GCH-Tg mouse lung, suggesting that inhibition of DHFR in BH4-deficient states leads to eNOS uncoupling. Taken together, these data reveal a key role for DHFR in regulating the BH4 vs BH2 ratio and eNOS coupling under conditions of low total biopterin availability in vivo.
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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.