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J. Biol. Chem., Vol. 276, Issue 1, 40-47, January 5, 2001
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From the Ascorbic acid has been shown to
stimulate endothelial nitric oxide (NO) synthesis in a time- and
concentration-dependent fashion without affecting NO
synthase (NOS) expression or L-arginine uptake. The
present study investigates if the underlying mechanism is related to
the NOS cofactor tetrahydrobiopterin. Pretreatment of human umbilical
vein endothelial cells with ascorbate (1 µM to 1 mM, 24 h) led to an up to 3-fold increase of
intracellular tetrahydrobiopterin levels that was
concentration-dependent and saturable at 100 µM.
Accordingly, the effect of ascorbic acid on
Ca2+-dependent formation of citrulline
(co-product of NO) and cGMP (product of the NO-activated soluble
guanylate cyclase) was abolished when intracellular tetrahydrobiopterin
levels were increased by coincubation of endothelial cells with
sepiapterin (0.001-100 µM, 24 h). In contrast,
ascorbic acid did not modify the pterin affinity of endothelial NOS,
which was measured in assays with purified tetrahydrobiopterin-free
enzyme. The ascorbate-induced increase of endothelial
tetrahydrobiopterin was not due to an enhanced synthesis of the
compound. Neither the mRNA expression of the rate-limiting enzyme
in tetrahydrobiopterin biosynthesis, GTP cyclohydrolase I, nor the
activities of either GTP cyclohydrolase I or
6-pyruvoyl-tetrahydropterin synthase, the second enzyme in the de
novo synthesis pathway, were altered by ascorbate. Our data
demonstrate that ascorbic acid leads to a chemical stabilization of
tetrahydrobiopterin. This was evident as an increase in the half-life
of tetrahydrobiopterin in aqueous solution. Furthermore, the increase
of tetrahydrobiopterin levels in intact endothelial cells coincubated
with cytokines and ascorbate was associated with a decrease of more
oxidized biopterin derivatives (7,8-dihydrobiopterin and biopterin) in
cells and cell supernatants. The present study suggests that saturated
ascorbic acid levels in endothelial cells are necessary to protect
tetrahydrobiopterin from oxidation and to provide optimal conditions
for cellular NO synthesis.
L-Ascorbic Acid Potentiates Endothelial Nitric Oxide
Synthesis via a Chemical Stabilization of Tetrahydrobiopterin*
§,
, and
Center of Vascular Biology and Medicine,
Friedrich-Schiller-University of Jena, D-99089 Erfurt, Germany, the
¶ Institute for Pharmacology and Toxicology,
Karl-Franzens-University, A-8010 Graz, Austria, and the
Institute for Medical Chemistry and Biochemistry, University of
Innsbruck, A-6020 Innsbruck, Austria
*
This work was supported by a grant from the Verbund
für klinische Forschung, Klinikum der
Friedrich-Schiller-Universität Jena (to R. H.) and by
Austrian research funds "Zur Förderung der wissenschaftlichen
Forschung" Project 13793-MOB (to E. R. W.) and Project
P13586-MED (to B. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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