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Cited by 104Nitric Oxide and Endothelin EffectsCancer-related gene regulationMetal-Catalyzed Oxygenation Mechanisms

Regulation of eNOS-Derived Superoxide by Endogenous Methylarginines

Druhan, Lawrence J., Forbes, Scott P., Pope, Arthur J., Chen, Chun-An, Zweier, Jay L., Cardounel, Arturo J.·2008·Biochemistry
DOI 10.1021/bi702377a
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Abstract

The endogenous methylarginines, asymmetric dimethylarginine (ADMA) and N (G)-monomethyl- l-arginine (L-NMMA) regulate nitric oxide (NO) production from endothelial NO synthase (eNOS). Under conditions of tetrahydrobiopterin (BH 4) depletion eNOS also generates (*)O 2 (-); however, the effects of methylarginines on eNOS-derived (*)O 2 (-) generation are poorly understood. Therefore, using electron paramagnetic resonance spin trapping techniques we measured the dose-dependent effects of ADMA and L-NMMA on (*)O 2 (-) production from eNOS under conditions of BH 4 depletion. In the absence of BH 4, ADMA dose-dependently increased NOS-derived (*)O 2 (-) generation, with a maximal increase of 151% at 100 microM ADMA. L-NMMA also dose-dependently increased NOS-derived (*)O 2 (-), but to a lesser extent, demonstrating a 102% increase at 100 microM L-NMMA. Moreover, the native substrate l-arginine also increased eNOS-derived (*)O 2 (-), exhibiting a similar degree of enhancement as that observed with ADMA. Measurements of NADPH consumption from eNOS demonstrated that binding of either l-arginine or methylarginines increased the rate of NADPH oxidation. Spectrophotometric studies suggest, just as for l-arginine and L-NMMA, the binding of ADMA shifts the eNOS heme to the high-spin state, indicative of a more positive heme redox potential, enabling enhanced electron transfer from the reductase to the oxygenase site. These results demonstrate that the methylarginines can profoundly shift the balance of NO and (*)O 2 (-) generation from eNOS. These observations have important implications with regard to the therapeutic use of l-arginine and the methylarginine-NOS inhibitors in the treatment of disease.

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  • In conditions that promote uncoupling, the heme group is usually the main generator of superoxide species through the formation of a ferrous/oxy complex that decays to ferric heme and superoxide.

    “In conditions that promote uncoupling, the heme group is usually the main generator of superoxide species through the formation of a ferrous/oxy complex that decays to ferric heme and superoxide (Eq. 20) (FIGURE 11) (250, 901, 973, 1033).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [250]

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Authors
Druhan, L. J., Forbes, S. P., Pope, A. J., Chen, C.-A., Zweier, J. L., & Cardounel, A. J.
Affiliations
University of Florida Health (US)
Corresponding author
Cardounel, Arturo J.
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2008-06-14
Volume
47
Issue
27
Pages
7256-7263
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi702377a
OpenAlex
W2021836259
Cited by
104
References
54
Citations by year
2024: 1 · 2023: 3 · 2022: 8 · 2021: 4 · 2020: 1 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 9 · 2015: 7 · 2014: 8 · 2013: 13 · 2012: 10
FWCI
6.56
Type
journal article
Language
en
Open access
closed
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL081734, HL-38324, HL063744, R01HL063744, HL090027, HL081734, F31HL090027)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Keywords
endothelial nitric oxide synthase, superoxide production, asymmetric dimethylarginine, L-NMMA, L-arginine, heme redox state, NADPH consumption, nitric oxide, electron transfer
MeSH terms
Arginine, Biopterins, Electron Spin Resonance Spectroscopy, Heme, Humans, NADP, Superoxides, omega-N-Methylarginine, Nitric Oxide Synthase Type III

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