Cited by 213Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressNeutrophil, Myeloperoxidase and Oxidative Mechanisms

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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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Crabtree, Mark J., Smith, Caroline L., Lam, George, Goligorsky, Michael S., Gross, Steven S.·2008·American Journal of Physiology-Heart and Circulatory Physiology

DOI 10.1152/ajpheart.00823.2007PMC PMC2722919

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Abstract

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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Authors: Crabtree, M. J., Smith, C. L., Lam, G., Goligorsky, M. S., & Gross, S. S.
Affiliations: Cornell University (US)
ORCID: Crabtree, Mark J.
Smith, Caroline L.
Goligorsky, Michael S.
Gross, Steven S.
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
DOI: 10.1152/ajpheart.00823.2007
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 (medical) › 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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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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