Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity

Livius V. d'Uscio, Sheldon Milstien, Darcy Richardson, Leslie Smith, Zvonimir S. Katusic

Research output: Contribution to journalArticle

216 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)88-95
Number of pages8
JournalCirculation research
Volume92
Issue number1
DOIs
StatePublished - Jan 10 2003

Keywords

  • Antioxidants
  • Nitric oxide
  • Nitric oxide synthase
  • Superoxide anion
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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