ArticleProceedings of the National Academy of Sciences of the United States of America2005
Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 173 papers.
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Who cites it
173 citing papers in PubMed.
- A novel hydrogen sulfide prodrug, SG1002, promotes hydrogen sulfide and nitric oxide bioavailability in heart failure patients.Cardiovascular therapeutics · 2015Trial
- Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease.Circulation · 2012Trial
- Renin-Angiotensin System Activation Drives Early Cardiorenal Dysfunction in Normotensive Prediabetes.Endocrinology, diabetes & metabolism · 2026Article
- Blocking MyD88 Signaling Pathway Protects Against Myocardial Ischemia Reperfusion by Inhibiting NOX/ROS Pathway and Enhancing eNOS Activity.International journal of molecular sciences · 2026Article
- The core mechanism of hypertension-linked renal fibrosis: "RAAS-ROS-inflammation-fibrosis" axis.iScience · 2026Review
- eNOS Uncoupling-ER Stress-Mitochondrial Dysfunction Axis in the Development of Pulmonary Hypertension.JACC. Basic to translational science · 2026Article
- The Link Between Venous and Arterial Thrombosis: Is There a Role for Endothelial Dysfunction?Cells · 2025Review
- Promotion of nitric oxide production: mechanisms, strategies, and possibilities.Frontiers in physiology · 2025Review
- NO/NOS system dysregulation as a key molecular mechanism in chemotherapy-induced cardiotoxicity: a review.Frontiers in cardiovascular medicine · 2025Review
- Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR.Circulation research · 2024Article
- Combination of Methotrexate and Resveratrol Reduces Pro-Inflammatory Chemokines in Human THP-1 Cells.Journal of inflammation research · 2024Article
- The role of oxidative stress in aortic dissection: a potential therapeutic target.Frontiers in cardiovascular medicine · 2024Review
- Intracellular delivery of nitric oxide enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.Science advances · 2023Article
- Research Progress of Flavonoids Regulating Endothelial Function.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Impact of l-citrulline on nitric oxide signaling and arginase activity in hypoxic human pulmonary artery endothelial cells.Pulmonary circulation · 2023Article
- Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets.Cellular & molecular biology letters · 2023Article
- Based on network pharmacology and bioinformatics to analyze the mechanism of action of Astragalus membranaceus in the treatment of vitiligo and COVID-19.Scientific reports · 2023Article
- YAP-galectin-3 signaling mediates endothelial dysfunction in angiotensin II-induced hypertension in mice.Cellular and molecular life sciences : CMLS · 2023Article
- Intravenous Injection of Na Ions Aggravates Ang II-Induced Hypertension-Related Vascular Endothelial Injury by Increasing Transmembrane Osmotic Pressure.International journal of nanomedicine · 2023Article
- Increased NOX2 expression in astrocytes leads to eNOS uncoupling through dihydrofolate reductase in endothelial cells after subarachnoid hemorrhage.Frontiers in molecular neuroscience · 2023Article
113 more citing papers are in PubMed but not listed here.
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2 authors.
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Abstract
Recent studies demonstrate that oxidative inactivation of tetrahydrobiopterin (H4B) may cause uncoupling of endothelial nitric oxide synthase (eNOS) to produce superoxide (O2*-). H4B was found recyclable from its oxidized form by dihydrofolate reductase (DHFR) in several cell types. Functionality of the endothelial DHFR, however, remains completely unknown. Here we present findings that specific inhibition of endothelial DHFR by RNA interference markedly reduced endothelial H4B and nitric oxide (NO.) bioavailability. Furthermore, angiotensin II (100 nmol/liter for 24 h) caused a H4B deficiency that was mediated by H2O2-dependent down-regulation of DHFR. This response was associated with a significant increase in endothelial O2*- production, which was abolished by eNOS inhibitor N-nitro-L-arginine-methyl ester or H2O2 scavenger polyethylene glycol-conjugated catalase, strongly suggesting H2O2-dependent eNOS uncoupling. Rapid and transient activation of endothelial NAD(P)H oxidases was responsible for the initial burst production of O2* (Rac1 inhibitor NSC 23766 but not an N-nitro-L-arginine-methyl ester-attenuated ESR O2*- signal at 30 min) in response to angiotensin II, preceding a second peak in O2*- production at 24 h that predominantly depended on uncoupled eNOS. Overexpression of DHFR restored NO. production and diminished eNOS production of O2*- in angiotensin II-stimulated cells. In conclusion, these data represent evidence that DHFR is critical for H4B and NO. bioavailability in the endothelium. Endothelial NAD(P)H oxidase-derived H2O2 down-regulates DHFR expression in response to angiotensin II, resulting in H4B deficiency and uncoupling of eNOS. This signaling cascade may represent a universal mechanism underlying eNOS dysfunction under pathophysiological conditions associated with oxidant stress.
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