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Cited by 392Hemoglobinopathies and Related DisordersNitric Oxide and Endothelin EffectsRedox biology and oxidative stress

Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease

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Aslan, Mutay, Ryan, Thomas M., Adler, Brian, Townes, Tim M., Parks, Dale A., Thompson, J. Anthony, Tousson, Albert, Gladwin, Mark T. +5 more·2001·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.221292098PMC PMC65009
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Abstract

Plasma xanthine oxidase (XO) activity was defined as a source of enhanced vascular superoxide (O \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{2}^{{\cdot}-}}}\end{equation*}\end{document} ) and hydrogen peroxide (H 2 O 2 ) production in both sickle cell disease (SCD) patients and knockout-transgenic SCD mice. There was a significant increase in the plasma XO activity of SCD patients that was similarly reflected in the SCD mouse model. Western blot and enzymatic analysis of liver tissue from SCD mice revealed decreased XO content. Hematoxylin and eosin staining of liver tissue of knockout-transgenic SCD mice indicated extensive hepatocellular injury that was accompanied by increased plasma content of the liver enzyme alanine aminotransferase. Immunocytochemical and enzymatic analysis of XO in thoracic aorta and liver tissue of SCD mice showed increased vessel wall and decreased liver XO, with XO concentrated on and in vascular luminal cells. Steady-state rates of vascular O \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{2}^{{\cdot}-}}}\end{equation*}\end{document} production, as indicated by coelenterazine chemiluminescence, were significantly increased, and nitric oxide ( ⋅ NO)-dependent vasorelaxation of aortic ring segments was severely impaired in SCD mice, implying oxidative inactivation of ⋅ NO. Pretreatment of aortic vessels with the superoxide dismutase mimetic manganese 5,10,15,20-tetrakis( N -ethylpyridinium-2-yl)porphyrin markedly decreased O \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{2}^{{\cdot}-}}}\end{equation*}\end{document} levels and significantly restored acetylcholine-dependent relaxation, whereas catalase had no effect. These data reveal that episodes of intrahepatic hypoxia-reoxygenation associated with SCD can induce the release of XO into the circulation from the liver. This circulating XO can then bind avidly to vessel luminal cells and impair vascular function by creating an oxidative milieu and catalytically consuming ⋅ NO via O \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{2}^{{\cdot}-}}}\end{equation*}\end{document} -dependent mechanisms.

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Authors
Aslan, M., Ryan, T. M., Adler, B., Townes, T. M., Parks, D. A., Thompson, J. A., Tousson, A., Gladwin, M. T., Patel, R. P., Tarpey, M. M., Batinic-Haberle, I., White, C. R., & Freeman, B. A.
Affiliations
  • National Institutes of Health (US)
  • Departments of Anesthesiology, Biochemistry and Molecular Genetics, Pathology, Medicine, and Surgery, Center for Free Radical Biology, Imaging Facility and Comprehensive Sickle Cell Disease Center, University of Alabama, Birmingham, AL 35233; Critical Care Medicine Department of the Warren G. Magnuson Clinical Center, and Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; and Department of...
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2001-12-18
Volume
98
Issue
26
Pages
15215-15220
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.221292098
PMC
PMC65009
OpenAlex
W2014093734
Cited by
391
References
67
Citations by year
2026: 4 · 2025: 5 · 2024: 5 · 2023: 12 · 2022: 9 · 2021: 14 · 2020: 14 · 2019: 18 · 2018: 15 · 2017: 14 · 2016: 9 · 2015: 17 · 2014: 17 · 2013: 16 · 2012: 11
FWCI
9.84
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p60hl058418-05)
  • National Heart, Lung, and Blood Institute (R01HL64937, R01HL064937, P6-HL-58418, R01HL058115, R01-HL-58115)
Topics
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
sickle cell disease, xanthine oxidase, superoxide, nitric oxide, hydrogen peroxide, hepatocyte injury, aorta, superoxide dismutase mimetic, manganese porphyrin
MeSH terms
Alanine Transaminase, Anemia, Sickle Cell, Animals, Endothelium, Vascular, Erythrocytes, Humans, Muscle Relaxation, Nitric Oxide, Superoxides, Xanthine Oxidase, Mice, Knockout, Mice, In Vitro Techniques

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