title: Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity.
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.
authors.affiliation: Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, Minn 55905, USA.
authors.forename: Livius V
authors.initials: LV
authors.lastname: d'Uscio
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.forename: Darcy
authors.initials: D
authors.lastname: Richardson
authors.forename: Leslie
authors.initials: L
authors.lastname: Smith
authors.forename: Zvonimir S
authors.initials: ZS
authors.lastname: Katusic
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D001205:Ascorbic Acid / Q000097:blood / Q000494:pharmacology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013481:Superoxides / Q000378:metabolism; D013995:Time; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014666:Vasomotor System / Q000187:drug effects; D014810:Vitamin E / Q000097:blood / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D013481:Superoxides; D014810:Vitamin E; D001708:Biopterins; C002744:3-nitrotyrosine; D014443:Tyrosine; C017226:7,8-dihydrobiopterin; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C003402:sapropterin; D006152:Cyclic GMP; D001205:Ascorbic Acid