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.
Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease
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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:
Proceedings of the National Academy of Sciences, 2001
Erschienen in:Proceedings of the National Academy of Sciences
Beschreibung:
<jats:p>
Plasma xanthine oxidase (XO) activity was defined as a source
of enhanced vascular superoxide (O
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) 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
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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
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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
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-dependent mechanisms.
</jats:p>