• Medientyp: E-Artikel
  • Titel: Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease
  • Beteiligte: Aslan, Mutay; Ryan, Thomas M.; Adler, Brian; Townes, Tim M.; Parks, Dale A.; Thompson, J. Anthony; Tousson, Albert; Gladwin, Mark T.; Patel, Rakesh P.; Tarpey, Margaret M.; Batinic-Haberle, Ines; White, C. Roger; Freeman, Bruce A.
  • Erschienen in: Proceedings of the National Academy of Sciences
  • Erschienen: Proceedings of the National Academy of Sciences, 2001
  • Sprache: Englisch
  • DOI: 10.1073/pnas.221292098
  • ISSN: 0027-8424; 1091-6490
  • Schlagwörter: Multidisciplinary
  • Zusammenfassung: <jats:p> Plasma xanthine oxidase (XO) activity was defined as a source of enhanced vascular superoxide (O <jats:inline-formula> <jats:tex-math notation="LaTeX">\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}</jats:tex-math> </jats:inline-formula> ) and hydrogen peroxide (H <jats:sub>2</jats:sub> O <jats:sub>2</jats:sub> ) 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 <jats:inline-formula> <jats:tex-math notation="LaTeX">\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}</jats:tex-math> </jats:inline-formula> production, as indicated by coelenterazine chemiluminescence, were significantly increased, and nitric oxide ( <jats:sup>⋅</jats:sup> NO)-dependent vasorelaxation of aortic ring segments was severely impaired in SCD mice, implying oxidative inactivation of <jats:sup>⋅</jats:sup> NO. Pretreatment of aortic vessels with the superoxide dismutase mimetic manganese 5,10,15,20-tetrakis( <jats:italic>N</jats:italic> -ethylpyridinium-2-yl)porphyrin markedly decreased O <jats:inline-formula> <jats:tex-math notation="LaTeX">\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}</jats:tex-math> </jats:inline-formula> 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 <jats:sup>⋅</jats:sup> NO via O <jats:inline-formula> <jats:tex-math notation="LaTeX">\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}</jats:tex-math> </jats:inline-formula> -dependent mechanisms. </jats:p>
  • Beschreibung: <jats:p>
    Plasma xanthine oxidase (XO) activity was defined as a source
    of enhanced vascular superoxide (O
    <jats:inline-formula>
    <jats:tex-math notation="LaTeX">\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}</jats:tex-math>
    </jats:inline-formula>
    ) and
    hydrogen peroxide (H
    <jats:sub>2</jats:sub>
    O
    <jats:sub>2</jats:sub>
    ) 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
    <jats:inline-formula>
    <jats:tex-math notation="LaTeX">\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}</jats:tex-math>
    </jats:inline-formula>
    production, as indicated by coelenterazine
    chemiluminescence, were significantly increased, and nitric oxide
    (
    <jats:sup>⋅</jats:sup>
    NO)-dependent vasorelaxation of aortic ring segments was
    severely impaired in SCD mice, implying oxidative inactivation of
    <jats:sup>⋅</jats:sup>
    NO. Pretreatment of aortic vessels with the superoxide
    dismutase mimetic manganese
    5,10,15,20-tetrakis(
    <jats:italic>N</jats:italic>
    -ethylpyridinium-2-yl)porphyrin
    markedly decreased O
    <jats:inline-formula>
    <jats:tex-math notation="LaTeX">\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}</jats:tex-math>
    </jats:inline-formula>
    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
    <jats:sup>⋅</jats:sup>
    NO via
    O
    <jats:inline-formula>
    <jats:tex-math notation="LaTeX">\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}</jats:tex-math>
    </jats:inline-formula>
    -dependent mechanisms.
    </jats:p>
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