Ratio of 5,6,7,8-tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS
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5,6,7,8-Tetrahydrobiopterin (BH 4 ) is an essential cofactor of nitric oxide synthases (NOSs). Oxidation of BH 4 , in the setting of diabetes and other chronic vasoinflammatory conditions, can cause cofactor insufficiency and uncoupling of endothelial NOS (eNOS), manifest by a switch from nitric oxide (NO) to superoxide production. Here we tested the hypothesis that eNOS uncoupling is not simply a consequence of BH 4 insufficiency, but rather results from a diminished ratio of BH 4 vs. its catalytically incompetent oxidation product, 7,8-dihydrobiopterin (BH 2 ). In support of this hypothesis, [ 3 H]BH 4 binding studies revealed that BH 4 and BH 2 bind eNOS with equal affinity ( K d ≈ 80 nM) and BH 2 can rapidly and efficiently replace BH 4 in preformed eNOS-BH 4 complexes. Whereas the total biopterin pool of murine endothelial cells (ECs) was unaffected by 48-h exposure to diabetic glucose levels (30 mM), BH 2 levels increased from undetectable to 40% of total biopterin. This BH 2 accumulation was associated with diminished calcium ionophore-evoked NO activity and accelerated superoxide production. Since superoxide production was suppressed by NOS inhibitor treatment, eNOS was implicated as a principal superoxide source. Importantly, BH 4 supplementation of ECs (in low and high glucose-containing media) revealed that calcium ionophore-evoked NO bioactivity correlates with intracellular BH 4 :BH 2 and not absolute intracellular levels of BH 4 . Reciprocally, superoxide production was found to negatively correlate with intracellular BH 4 :BH 2 . Hyperglycemia-associated BH 4 oxidation and NO insufficiency was recapitulated in vivo, in the Zucker diabetic fatty rat model of type 2 diabetes. Together, these findings implicate diminished intracellular BH 4 :BH 2 , rather than BH 4 depletion per se, as the molecular trigger for NO insufficiency in diabetes.
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eNOS shows almost identical binding affinities for BH4 and BH2, and is thus very sensitive to imbalances in the concentrations of BH4 and BH2.
“iNOS and nNOS show higher affinity toward BH4 than for BH2 (around 10-fold in the absence of l-arginine) (6, 514, 753); however, eNOS shows almost identical binding affinities for BH4 and BH2, and it is thus very sensitive to imbalances in the concentrations of BH4 and BH2 (190).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [190]
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 [190]
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- Authors
- Crabtree, M. J., Smith, C. L., Lam, G., Goligorsky, M. S., & Gross, S. S.
- Affiliations
- Cornell University (US)
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2008-04
- Volume
- 294
- Issue
- 4
- Pages
- H1530-H1540
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC2722919
- OpenAlex
- W2148390554
- Cited by
- 213
- References
- 62
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 8 · 2019: 5 · 2018: 12 · 2017: 9 · 2016: 20 · 2015: 13 · 2014: 13 · 2013: 20 · 2012: 15
- FWCI
- 12.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL046403, HL87062, R37HL087062, R01HL080702, HL-46403)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK045462, DK 45462)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- tetrahydrobiopterin, 7,8-dihydrobiopterin, eNOS uncoupling, nitric oxide production, superoxide production, endothelial cells, hyperglycemia, type 2 diabetes, BH4 supplementation, calcium ionophore, Zucker diabetic fatty rats
- MeSH terms
- Animals, Biopterins, Blood Glucose, Cell Line, Diabetes Mellitus, Type 2, Disease Models, Animal, Enzyme Inhibitors, Glucose, Glutathione, Mitochondria, Nitric Oxide, Oxidation-Reduction, Protein Binding, Rats, Zucker, Superoxides, Time Factors, Tritium, NG-Nitroarginine Methyl Ester, Endothelial Cells, Mice, Rats, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III
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