Circulation Research. 2002
Published online before print December 2, 2002, doi: 10.1161/01.RES.0000049166.33035.62
Published online before print December 2, 2002, doi: 10.1161/01.RES.0000049166.33035.62
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Submitted on July 30, 2002
Revised on November 15, 2002
Accepted on November 15, 2002
Long-Term Vitamin C Treatment Increases Vascular Tetrahydrobiopterin Levels and Nitric Oxide Synthase Activity
Livius V. d'Uscio ;
From the Departments of Anesthesiology, and Molecular Pharmacology and Experimental Therapeutics (L.V.d'.U., D.R., L.S., Z.S.K.), Mayo Clinic and Foundation, Rochester, Minn; and the National Institute of Mental Health (S.M.), NIH, Bethesda, Md.
* To whom correspondence should be addressed. E-mail: katusic.zvonimir{at}mayo.edu.
In cultured endothelial cells, the antioxidant, L-ascorbic acid (vitamin C), increases nitric oxide synthase (NOS) enzyme activity via chemical stabilization of tetrahydrobiopterin. Our objective was to determine the effect of vitamin C on NOS function and tetrahydrobiopterin metabolism in vivo. Twenty-six to twenty-eight weeks of diet supplementation with vitamin C (1%/kg chow) significantly increased circulating levels of vitamin C in wild-type (C57BL/6J) and apolipoprotein E (apoE)-deficient mice. Measurements of NOS enzymatic activity in aortas of apoE-deficient mice indicated a significant increase in total NOS activity. However, this increase was mainly due to high activity of inducible NOS, whereas eNOS activity was reduced. Significantly higher tetrahydrobiopterin levels were detected in aortas of apoE-deficient mice. Long-term treatment with vitamin C restored endothelial NOS activity in aortas of apoE-deficient mice, but did not affect activity of inducible NOS. In addition, 7,8-dihydrobiopterin levels, an oxidized form of tetrahydrobiopterin, were decreased and vascular endothelial function of aortas was significantly improved in apoE-deficient mice. Interestingly, vitamin C also increased tetrahydrobiopterin and NOS activity in aortas of C57BL/6J mice. In contrast, long-term treatment with vitamin E (2000 U/kg chow) did not affect vascular NOS activity or metabolism of tetrahydrobiopterin. In vivo, beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity. In contrast, vitamin E does not affect tetrahydrobiopterin metabolism or eNOS activity.
Key words: tetrahydrobiopterin • nitric oxide synthase • nitric oxide • antioxidants • superoxide anion
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