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J Biol Chem, Vol. 274, Issue 12, 8254-8260, March 19, 1999
From the Center of Vascular Biology and Medicine,
Friedrich-Schiller-University of Jena, 99089 Erfurt, Germany
Ascorbic acid has been shown to enhance impaired
endothelium-dependent vasodilation in patients with
atherosclerosis by a mechanism that is thought to involve protection of
nitric oxide (NO) from inactivation by free oxygen radicals. The
present study in human endothelial cells from umbilical veins and
coronary arteries investigates whether L-ascorbic
acid additionally affects cellular NO synthesis. Endothelial cells were
incubated for 24 h with 0.1-100 µM ascorbic acid
and were subsequently stimulated for 15 min with ionomycin (2 µM) or thrombin (1 unit/ml) in the absence of
extracellular ascorbate. Ascorbate pretreatment led to a 3-fold
increase of the cellular production of NO measured as the formation of
its co-product citrulline and as the accumulation of its effector molecule cGMP. The effect was saturated at 100 µM and
followed a similar kinetics as seen for the uptake of ascorbate into
the cells. The investigation of the precursor molecule
L-gulonolactone and of different ascorbic acid derivatives
suggests that the enediol structure of ascorbate is essential for its
effect on NO synthesis. Ascorbic acid did not induce the expression of
the NO synthase (NOS) protein nor enhance the uptake of the NOS
substrate L-arginine into endothelial cells. The ascorbic
acid effect was minimal when the citrulline formation was measured in
cell lysates from ascorbate-pretreated cells in the presence of known
cofactors for NOS activity. However, when the cofactor
tetrahydrobiopterin was omitted from the assay, a similar potentiating
effect of ascorbate pretreatment as seen in intact cells was
demonstrated, suggesting that ascorbic acid may either enhance the
availability of tetrahydrobiopterin or increase its affinity for the
endothelial NOS. Our data suggest that intracellular ascorbic acid
enhances NO synthesis in endothelial cells and that this may explain,
in part, the beneficial vascular effects of ascorbic acid.
L-Ascorbic Acid Potentiates Nitric Oxide Synthesis in
Endothelial Cells
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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