Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 24, Issue 3, 2004, Pages 413-420

  Alp, Nicholas J ^a   Channon, Keith M ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Nitric oxide synthase; Superoxide; Tetrahydrobiopterin

Indexed keywords

ENDOTHELIAL NITRIC OXIDE SYNTHASE; GUANOSINE TRIPHOSPHATE CYCLOHYDROLASE I; NITRIC OXIDE; REACTIVE OXYGEN METABOLITE; SUPEROXIDE; TETRAHYDROBIOPTERIN;

ANIMAL MODEL; BIOAVAILABILITY; GCH1 GENE; GENE; HOMEOSTASIS; OXIDATION; PRIORITY JOURNAL; REGULATORY MECHANISM; SHORT SURVEY; SIGNAL TRANSDUCTION; VASCULAR DISEASE;

ANIMALS; BIOLOGICAL AVAILABILITY; BIOPTERIN; COENZYMES; DIABETES MELLITUS; ENZYME INDUCTION; GTP CYCLOHYDROLASE; HUMANS; HYPERCHOLESTEROLEMIA; HYPERTENSION; MICE; MICE, MUTANT STRAINS; MODELS, ANIMAL; NITRIC OXIDE; NITRIC OXIDE SYNTHASE; NITRIC OXIDE SYNTHASE TYPE II; NITRIC OXIDE SYNTHASE TYPE III; OXIDATION-REDUCTION; OXIDATIVE STRESS; PTERINS; RABBITS; RATS; RATS, INBRED STRAINS; SUPEROXIDES; VASCULAR DISEASES;

EID: 1542283780     PISSN: 10795642     EISSN: None     Source Type: Journal    
DOI: 10.1161/01.ATV.0000110785.96039.f6     Document Type: Short Survey

References (106)

1. Ignarro LJ. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J Physiol Pharmacol. 2002;53:503-514.
2. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376.
3. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987;84:9265-9269.
4. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23:168-175.
5. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001;104:2673-2678.
6. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899-1906.
7. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000;87:840-844.
8. Thony B, Auerbach G, Blau N. Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J. 2000;347(pt 1):1-16.
9. Kaspers B, Gutlich M, Witter K, Losch U, Goldberg M, Ziegler I. Coordinate induction of tetrahydrobiopterin synthesis and nitric oxide synthase activity in chicken macrophages: upregulation of GTP-cyclohydrolase I activity. Comp Biochem Physiol B Biochem Mol Biol. 1997;117:209-215.
10. Werner ER, Werner-Felmayer G, Fuchs D, et al. Biochemistry and function of pteridine synthesis in human and murine macrophages. Palhobiology. 1991;59:276-279.
11. Gupta S, Fredericks S, Schwartzman RA, Holt DW, Kaski JC. Serum neopterin in acute coronary syndromes. Lancet. 1997;349:1252-1253.
12. Woo HJ, Kang JY, Choi YK, Park YS. Production of sepiapterin in Escherichia coli by coexpression of cyanobacterial GTP cyclohydrolase I and human 6-pyruvoyltetrahydropterin synthase. Appl Environ Microbiol. 2002;68:3138-3140.
13. Krivi GG, Brown GM. Purification and properties of the enzymes from Drosophila melanogaster that catalyze the synthesis of sepiapterin from dihydroneopterin triphosphate. Biochem Genet. 1979;17:371-390.
14. Zorzi G, Redweik U, Trippe H, Penzien JM, Thony B, Blau N. Detection of sepiapterin in CSF of patients with sepiapterin reductase deficiency. Mol Genet Metab. 2002;75:174-177.
15. Nichol CA, Lee CL, Edelstein MP, Chao JY, Duch DS. Biosynthesis of tetrahydrobiopterin by de novo and salvage pathways in adrenal medulla extracts, mammalian cell cultures, and rat brain in vivo. Proc Natl Acad Sci U S A. 1983;80:1546-1550.
16. Hauer CR, Rebrin I, Thony B, et al. Phenylalanine hydroxylase-stimulating protein/pterin-4 alpha-carbinolamine dehydratase from rat and human liver: purification, characterization, and complete amino acid sequence. J Biol Chem. 1993;268:4828-4831.
17. Davis MD, Kaufman S, Milstien S. Distribution of 4a-hydroxytetrahydropterin dehydratase in rat tissues: comparison with the aromatic amino acid hydroxylases. FEBS Lett. 1992;302:73-76.
18. Vasquez-Vivar J, Whitsett J, Martasek P, Hogg N, Kalyanaraman B. Reaction of tetrahydrobiopterin with superoxide: EPR-kinetic analysis and characterization of the pteridine radical. Free Radic Biol Med. 2001;31:975-985.
19. Scriver CR, Eisensmith RC, Woo SL, Kaufman S. The hyperphenylalaninemias of man and mouse. Annu Rev Genet. 1994;28:141-165.
20. Smith I, Clayton BE, Wolff OH. New variant of phenylketonuria with progressive neurological illness unresponsive to phenylalanine restriction. Lancet. 1975;1:1108-1111.
21. Thony B, Blau N. Mutations in the GTP cyclohydrolase I and 6-pyruvoyltetrahydropterin synthase genes. Hum Mutat. 1997;10:11-20.
22. Dianzani I, de Sanctis L, Smooker PM, et al. Dihydropteridine reductase deficiency: physical structure of the QDPR gene, identification of two new mutations and genotype-phenotype correlations. Hum Mutat. 1998;12:267-273.
23. Segawa M, Hosaka A, Miyagawa F, Nomura Y, Imai H. Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol. 1976;14:215-233.
24. Ichinose H, Suzuki T, Inagaki H, Ohye T, Nagatsu T. Molecular genetics of dopa-responsive dystonia. Biol Chem. 1999;380:1355-1364.
25. Nar H, Huber R, Meining W, Schmid C, Weinkauf S, Bacher A. Atomic structure of GTP cyclohydrolase I. Structure. 1995;3:459-466.
26. Nar H, Huber R, Auerbach G, et al. Active site topology and reaction mechanism of GTP cyclohydrolase I. Proc Natl Acad Sci USA. 1995;92:12120-12125.
27. Katusic ZS, Stelter A, Milstien S. Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol. 1998;18:27-32.
28. Linscheid P, Schaffner A, Blau N, Schoedon G. Regulation of 6-pyruvoyltetrahydropterin synthase activity and messenger RNA abundance in human vascular endothelial cells. Circulation. 1998;98:1703-1706.
29. Werner-Felmayer G, Werner ER, Fuchs D, et al. Pteridine biosynthesis in human endothelial cells: impact on nitric oxide-mediated formation of cyclic GMP. J Biol Chem. 1993;268:1842-1846.
30. Ishii M, Shimizu S, Nagai T, Shiota K, Kiuchi Y, Yamamoto T. Stimulation of tetrahydrobiopterin synthesis induced by insulin: possible involvement of phosphatidylinositol 3-kinase. Int J Biochem Cell Biol. 2001;33:65-73.
31. Lapize C, Pluss C, Werner ER, Huwiler A, Pfeilschifter J. Protein kinase C phosphorylates and activates GTP cyclohydrolase I in rat renal mesangial cells. Biochem Biophys Res Commun. 1998;251:802-805.
32. Milstien S, Jaffe H, Kowlessur D, Bonner TI. Purification and cloning of the GTP cyclohydrolase I feedback regulatory protein, GFRP. J Biol Chem. 1996;271:19743-19751.
33. Yoneyama T, Brewer JM, Hatakeyama K. GTP cyclohydrolase I feedback regulatory protein is a pentamer of identical subunits: purification, cDNA cloning, and bacterial expression. J Biol Chem. 1997;272:9690-9696.
34. Yoneyama T, Hatakeyama K. Decameric GTP cyclohydrolase I forms complexes with two pentameric GTP cyclohydrolase I feedback regulatory proteins in the presence of phenylalanine or of a combination of tetrahydrobiopterin and GTP. J Biol Chem. 1998;273:20102-20108.
35. Maita N, Okada K, Hirotsu S, Hatakeyama K, Hakoshima T. Preparation and crystallization of the stimulatory and inhibitory complexes of GTP cyclohydrolase I and its feedback regulatory protein GFRP. Schizophr Res. 2001;57:1153-1156.
36. Maita N, Okada K, Hatakeyama K, Hakoshima T. Crystal structure of the stimulatory complex of GTP cyclohydrolase I and its feedback regulatory protein GFRP. Proc Natl Acad Sci U S A. 2002;99:1212-1217.
37. Harada T, Kagamiyama H, Hatakeyama K. Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity. Science. 1993;260:1507-1510.
38. Michel JB, Feron O, Sacks D, Michel T. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem. 1997;272:15583-15586.
39. Prabhakar P, Thatte HS, Goetz RM, Cho MR, Golan DE, Michel T. Receptor-regulated translocation of endothelial nitric-oxide synthase. J Biol Chem. 1998;273:27383-27388.
40. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399:601-605.
41. Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1-R12.
42. Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells can transduce an atheroprotective force. Arterioscler Thromb Vcsc Biol. 1998;18:677-685.
43. Wilcox JN, Subramanian RR, Sundell CL, et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol. 1997;17:2479-2488.
44. Cosentino F, Hishikawa K, Katusic ZS, Luscher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation. 1997;96:25-28.
45. Bauersachs J, Bouloumi A, Fraccarollo D, Hu K, Busse R, Ertl G. Endothelial dysfunction in chronic myocardial infarction despite increased vascular endothelial nitric oxide synthase and soluble guanylate cyclase expression: role of enhanced vascular superoxide production. Circulation. 1999;100:292-298.
46. Bouloumie A, Bauersachs J, Linz W, et al. Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production. Hypertension. 1997;30:934-941.
47. Ozaki M, Kawashima S, Yamashita T, et al. Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest. 2002;110:331-340.
48. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000;86:494-501.
49. Vasquez-Vivar J, Kalyanaraman B, Martasek P, et al. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A. 1998;95:9220-9225.
50. Vasquez-Vivar J, Kalyanaraman B, Martasek P. The role of tetrahydrobiopterin in superoxide generation from eNOS: enzymology and physiological implications. Free Radic Res. 2003;37:121-127.
51. Guzik TJ, Mussa S, Gastaldi D, et al. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation. 2002;105:1656-1662.
52. Hestzer T, Yla-Herttuala S, Luoma J, et al. Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia: role of oxidized LDL. Circulation. 1996;93:1346-1353.
53. Landmesser U, Dikalov S, Price SR, et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003;111:1201-1209.
54. Munzel T, Li H, Mollnau H, et al. Effects of long-term nitroglycerin treatment on endothelial nitric oxide synthase (NOS III) gene expression, NOS III-mediated superoxide production, and vascular NO bioavailability. Circ Res. 2000;86:E7-E12.
55. Maier W, Cosentino F, Lutolf RB, et al. Tetrahydrobiopterin improves endothelial function in patients with coronary artery disease. J Cardiovasc Pharmacol. 2000;35:173-178.
56. Munzel T, Afanas'ev IB, Kleschyov AL, Harrison DG. Detection of superoxide in vascular tissue. Arterioscler Thromb Vasc Biol. 2002;22:1761-1768.
57. Song Y, Cardounel AJ, Zweier JL, Xia Y. Inhibition of superoxide generation from neuronal nitric oxide synthase by heat shock protein 90: implications in NOS regulation. Biochemistry. 2002;41:10616-10622.
58. Pritchard KA Jr, Ackerman AW, Gross ER, et al. Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase. J Biol Chem. 2001;276:17621-17624.
59. Stepp DW, Ou J, Ackerman AW, Welak S, Klick D, Pritchard KA Jr. Native LDL and minimally oxidized LDL differentially regulate superoxide anion in vascular endothelium in situ. Am J Physiol Heart Circ Physiol. 2002;283:H750-H759.
60. Vasquez-Vivar J, Martasek P, Whitsett J, Joseph J, Kalyanaraman B. The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study. Biochem J. 2002;362:733-739.
61. Hurshman AR, Krebs C, Edmondson DE, Huynh BH, Marletta MA. Formation of a pterin radical in the reaction of the heme domain of inducible nitric oxide synthase with oxygen. Biochemistry. 1999;38:15689-15696.
62. Schmidt PP, Lange R, Gorren AC, Werner ER, Mayer B, Andersson KK. Formation of a protonated trihydrobiopterin radical cation in the first reaction cycle of neuronal and endothelial nitric oxide synthase detected by electron paramagnetic resonance spectroscopy. J Biol Inorg Chem. 2001;6:151-158.
63. Stroes E, Hijmering M, van Zandvoort M, Wever R, Rabelink TJ, van Faassen EE. Origin of superoxide production by endothelial nitric oxide synthase. FEBS Lett. 1998;438:161-164.
64. Rodríguez-Crespo I, Gerber NC, de Montellano PRO. Endothelial nitric-oxide synthase. J Biol Chem. 1996;271:11462-11467.
65. Raman CS, Li H, Martasek P, Kral V, Masters BS, Poulos TL. Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Cell. 1998;95:939-950.
66. Chen PF, Tsai AL, Wu KK. Cysteine 99 of endothelial, nitric oxide synthase (NOS-III) is critical for tetrahydrobiopterin-dependent NOS-III stability and activity. Biochem Biophys Res Comm. 1995;215:1119-1129.
67. Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest. 2002;109:817-826.
68. Tzeng E, Billiar TR, Robbins PD, Loftus M, Stuehr DJ. Expression of human inducible nitric oxide synthase in a tetrahydrobiopterin (H4B)-deficient cell line: H4B promotes assembly of enzyme subunits into an active enzyme. Proc Natl Acad Sci U S A. 1995;92:11771-11775.
69. Wever RMF, van Dam T, van Rijn HJ, de Groot F, Rabelink TJ. Tetrahydrobiopterin regulates superoxide and nitric oxide generation by recombinant endothelial nitric oxide synthase. Biochem Biophys Res Commun. 1997;237:340-344.
70. Reif A, Frohlich LG, Kotsonis P, et al. Tetrahydrobiopterin inhibits monomerization and is consumed during catalysis in neuronal NO synthase. J Biol Chem. 1999;274:24921-24929.
71. Cai S, Alp NJ, McDonald D, Canevari L, Heales S, Channon KM. GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerization. Cardiovasc Res. 2002;55:838-849.
72. Meininger CJ, Marinos RS, Hatakeyama K, et al. Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. Biochem J. 2000;349:353-356.
73. Shinozaki K, Kashiwagi A, Nishio Y, et al. Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2-imbalance in insulin-resistant rat aorta. Diabetes. 1999;48:2437-2445.
74. Shinozaki K, Okamura T, Nishio Y, Kashiwagi A, Kikkawa R, Toda N. Evaluation of endothelial free radical release by vascular tension responses in insulin-resistant rat aorta. Eur J Pharmacol. 2000;394:295-299.
75. Shinozaki K, Nishio Y, Okamura T, et al. Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats. Circ Res. 2000;87:566-573.
76. Pieper GM. Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol. 1997;29:8-15.
77. Pannirselvam M, Verma S, Anderson TJ, Triggle CR. Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db -/-) mice: role of decreased tetrahydrobiopterin bioavailability. Br J Pharmacol. 2002;136:255-263.
78. Hong HJ, Hsiao G, Cheng TH, Yen MH. Supplementation with tetrahydrobiopterin suppresses the development of hypertension in spontaneously hypertensive rats. Hypertension. 2001;38:1044-1048.
79. Cosentino F, Patton S, d'Uscio LV, et al. Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats. J Clin Invest. 1998;101:1530-1537.
80. Cosentino F, Barker JE, Brand MP, et al. Reactive oxygen species mediate endothelium-dependent relaxations in tetrahydrobiopterin-deficient mice. Arterioscler Thromb Vasc Biol. 2001;21:496-502.
81. Laursen JB, Somers M, Kurz S, et al. Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation. 2001;103:1282-1288.
82. Stroes E, Kastelein J, Cosentino F, et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest. 1997;99:41-46.
83. Heitzer T, Krohn K, Albers S, Meinertz T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia. 2000;43:1435-1438.
84. Heitzer T, Brockhoff C, Mayer B, et al. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: evidence for a dysfunctional nitric oxide synthase. Circ Res. 2000;86:E36-E41.
85. Fukuda Y, Teragawa H, Matsuda K, Yamagata T, Matsuura H, Chayama K. Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolaemia. Heart. 2002;87:264-269.
86. Tsutsui M, Milstien S, Katusic ZS. Effect of tetrahydrobiopterin on endothelial function in canine middle cerebral arteries. Circ Res. 1996;79:336-342.
87. Vasquez-Vivar J, Duquaine D, Whitsett J, Kalyanaraman B, Rajagopalan S. Altered tetrahydrobiopterin metabolism in atherosclerosis: implications for use of oxidized tetrahydrobiopterin analogues and thiol antioxidants. Arterioscler Thromb Vasc Biol. 2002;22:1655-1661.
88. Alp NJ, Mussa S, Khoo J, et al. Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I over-expression. J Clin Invest. 2003;119:725-735.
89. Mitchell BM, Dorrance AM, Webb RC. GTP cyclohydrolase I downregulation contributes to glucocorticoid hypertension in rats. Hypertension. 2003;41:669-674.
90. Zheng J-S, Yang X-Q, Lookingland KJ, et al. Gene transfer of human guanosine 5′-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low renin hypertension. Circulation. 2003;108:1238-1245.
91. Huie RE, Padmaja S. The reaction of NO with superoxide. Free Radic Res Commun. 1993;18:195-199.
92. Milstien S, Katusic Z. Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function. Biochem Biophys Res Commun. 1999;263:681-684.
93. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. 2003;278:22546-22554.
94. Oelze M, Mollnau H, Hoffmann N, et al. Vasodilator-stimulated phosphoprotein serine 239 phosphorylation as a sensitive monitor of defective nitric oxide/cGMP signaling and endothelial dysfunction. Circ Res. 2000;87:999-1005.
95. Hink U, Li H, Mollnau H, et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001;88:E14-E22.
96. Heitzer T, Just H, Munzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation. 1996;94:6-9.
97. Ting HH, Timimi FK, Haley EA, Roddy MA, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation. 1997;95:2617-2622.
98. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996;97:22-28.
99. Timimi FK, Ting HH, Haley EA, Roddy MA, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1998;31:552-557.
100. Levine GN, Frei B, Koulouris SN, Gerhard MD, Keaney JF, Vita JA. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 1996;93:1107-1113.
101. Gokce N, Keaney JF Jr, Frei B, et al. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 1999;99:3234-3240.
102. d'Uscio LV, Milstien S, Richardson D, Smith L, Katusic ZS. Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res. 2003;92:88-95.
103. Heller R, Munscher-Paulig F, Grabner R, Till U. L-ascorbic acid potentiates nitric oxide synthesis in endothelial cells. J Biol Chem. 1999;274:8254-8260.
104. Huang A, Vita JA, Venema RC, Keaney J. Ascorbic acid enhances endothelial nitric oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem. 2000;275:17399-17406.
105. Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER. L-Ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem. 2001;276:40-47.
106. Patel KB, Stratford MR, Wardman P, Everett SA. Oxidation of tetrahydrobiopterin by biological radicals and scavenging of the trihydrobiopterin radical by ascorbate. Free Radic Biol Med. 2002;32:203-211.