Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease

Clinical Science

Volumn 113, Issue 1-2, 2007, Pages 47-63

  Schmidt, Tim S ^a   Alp, Nicholas J ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Atherosclerosis; Endothelium; Nitric oxide synthase (NOS); Tetrahydrobiopterin (BH4)

Indexed keywords

ENDOTHELIAL NITRIC OXIDE SYNTHASE; NITRIC OXIDE; SUPEROXIDE; TETRAHYDROBIOPTERIN;

ATHEROSCLEROSIS; BIOAVAILABILITY; DIABETES MELLITUS; DISEASE COURSE; ENDOTHELIAL DYSFUNCTION; ENZYME ACTIVITY; HOMEOSTASIS; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; NONHUMAN; OXIDATION; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; SYNTHESIS; SYSTEMATIC REVIEW; VASCULAR DISEASE; VASCULAR ENDOTHELIUM;

ANIMALS; ASCORBIC ACID; ATHEROSCLEROSIS; BIOPTERIN; DISEASE PROGRESSION; ENDOTHELIUM, VASCULAR; HOMEOSTASIS; HUMANS; NITRIC OXIDE; NITRIC OXIDE SYNTHASE TYPE III; OXIDATION-REDUCTION; REACTIVE OXYGEN SPECIES; VITAMINS;

EID: 34447536457     PISSN: 01435221     EISSN: None     Source Type: Journal    
DOI: 10.1042/CS20070108     Document Type: Review

References (170)

1. Cai, H. and Harrison, D. G. (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ. Res. 87, 840-844
2. Heitzer, T., Schlinzig, T., Krohn, K., Meinertz, T. and Munzel, T. (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104, 2673-2678
3. Ignarro, L. J. (2002) Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J. Physiol. Pharmacol. 53, 503-514
4. Hill, J. M., Zalos, G., Halcox, J. P. et al. (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N. Engl. J. Med. 348, 593-600
5. Panza, J. A., García, C. E., Kilcoyne, C. M., Quyyumi, A. A. and Cannon, III, R. O. (1995) Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation 91, 1732-1738
6. Schachinger, V., Britten, M. B., Elsner, M., Walter, D. H., Scharrer, I. and Zeiher, A. M. (1999) A positive family history of premature coronary artery disease is associated with impaired endothelium-dependent coronary blood flow regulation. Circulation 100, 1502-1508
7. Brevetti, G., Silvestro, A., Schiano, V. and Chiariello, M. (2003) Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation 108, 2093-2098
8. Halcox, J. P., Schenke, W. H., Zalos, G. et al. (2002) Prognostic value of coronary vascular endothelial dysfunction. Circulation 106, 653-658
9. Alp, N. J. and Channon, K. M. (2004) Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease. Arterioscler. Thromb. Vasc. Biol. 24, 413-420
10. Channon, K. M., Qian, H. S. and George, S. E. (2000) Nitric oxide synthase in atherosclerosis and vascular injury: insights from experimental gene therapy. Arterioscler. Thromb. Vasc. Biol. 20, 1873-1881
11. Ozaki, M., Kawashima, S., Yamashita, T. et al. (2002) Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J. Clin. Invest. 110, 331-340
12. Schulz, E., Tsilimingas, N., Rinze, R. et al. (2002) Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment. Circulation 105, 1170-1175
13. Furchgott, R. F. and Zawadzki, J. V. (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373-376
14. Ignarro, L. J., Buga, G. M., Wood, K. S., Byrns, R. E. and Chaudhuri, G. (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc. Natl. Acad. Sci. U.S.A. 84, 9265-9269
15. Palmer, R. M. J., Ferrige, A. G. and Moncada, S. (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327, 524-526
16. Palmer, R. M. J., Ashton, D. S. and Moncada, S. (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333, 664-666
17. Dawson, T. M. and Snyder, S. H. (1994) Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J. Neurosci. 14, 5147-5159
18. Ghosh, S. and Karin, M. (2002) Missing pieces in the NF-κB puzzle. Cell 109, (Suppl.), S81-S96
19. Bredt, D. S., Hwang, P. M. and Snyder, S. H. (1990) Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347, 768-770
20. Griffith, O. W. and Stuehr, D. J. (1995) Nitric oxide synthases: properties and catalytic mechanism. Annu. Rev. Physiol. 57, 707-736
21. Hevel, J. M., White, K. A. and Marletta, M. A. (1991) Purification of the inducible murine macrophage nitric oxide synthase. Identification as a flavoprotein. J. Biol. Chem. 266, 22789-22791
22. Hibbs, Jr, J. B., Taintor, R. R. and Vavrin, Z. (1987) Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science 235, 473-476
23. Stuehr, D. J. and Marletta, M. A. (1987) Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lymphokines, or interferon-γ. J. Immunol. 139, 518-525
24. Pollock, J. S., Forstermann, U., Mitchell, J. A. et al. (1991) Purification and characterization of particulate endothelium-derived relaxing factor synthetase from cultured and native bovine aortic endothelial cells. Proc. Natl. Acad. Sci. U.S.A. 88, 10480-10484
25. 2+- calmodulin and caveolin. J. Biol. Chem. 272, 15583-15586
26. Prabhakar, P., Thatte, H. S., Goetz, R. M., Cho, M. R., Golan, D. E. and Michel, T. (1998) Receptor-regulated translocation of endothelial nitric-oxide synthase. J. Biol. Chem. 273, 27383-27388
27. Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R. and Zeiher, A. M. (1999) Activation of nitric oxide synthase in endothelial cells by Akt- dependent phosphorylation. Nature 399, 601-605
28. Fleming, I. and Busse, R. (2003) Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1-R12
29. Traub, O. and Berk, B. C. (1998) Laminar shear stress: mechanisms by which endothelial cells can transduce an atheroprotective force. Arterioscler. Thromb. Vasc. Biol. 18, 677-685
30. Lam, C. F., Peterson, T. E., Richardson, D. M. et al. (2006) Increased blood flow causes coordinated upregulation of arterial eNOS and biosynthesis of tetrahydrobiopterin. Am. J. Physiol. Heart Circ. Physiol. 290, H786-H793
31. Wilcox, J. N., Subramanian, R. R., Sundell, C. L. et al. (1997) Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler. Thromb. Vasc. Biol. 17, 2479-2488
32. Cosentino, F., Hishikawa, K., Katusic, Z. S. and Luscher, T. F. (1997) High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 96, 25-28
33. Hink, U., Li, H., Mollnau, H. et al. (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ. Res. 88, E14-E22
34. Bauersachs, J., Bouloumi, A., Fraccarollo, D., Hu, K., Busse, R. and Ertl, G. (1999) 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 100, 292-298
35. Bouloumie, A., Bauersachs, J., Linz, W. et al. (1997) Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production. Hypertension 30, 934-941
36. Hopkins, F. G. (1895) The pigments of the pieridae: a contribution to the study of excretory substances which function in ornament. Phil. Trans. R. Soc. Lond. B 186, 661-682
37. Watt, W. B. (1964) Pteridine components of wing pigmentation in the butterfly colias eurytheme. Nature 201, 1326-1327
38. Kwon, N. S., Nathan, C. F. and Stuehr, D. J. (1989) Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages. J. Biol. Chem. 264, 20496-20501
39. Tayeh, M. A. and Marletta, M. A. (1989) Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor. J. Biol. Chem. 264, 19654-19658
40. Thony, B., Auerbach, G. and Blau, N. (2000) Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem. J. 347, 1-16
41. Katusic, Z. S., Stelter, A. and Milstien, S. (1998) Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells. Arterioscler. Thromb. Vasc. Biol. 18, 27-32
42. Linscheid, P., Schaffner, A., Blau, N. and Schoedon, G. (1998) Regulation of 6-pyruvoyltetrahydropterin synthase activity and messenger RNA abundance in human vascular endothelial cells. Circulation 98, 1703-1706
43. Huang, A., Zhang, Y. Y., Chen, K., Hatakeyama, K. and Keaney, Jr, J. F. (2005) Cytokine-stimulated GTP cyclohydrolase I expression in endothelial cells requires coordinated activation of nuclear factor-κB and Stat1/Stat3. Circ. Res. 96, 164-171
44. Werner-Felmayer, G., Werner, E. R., Fuchs, D. et al. (1993) Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP. J. Biol. Chem. 268, 1842-1846
45. Al Sarraj, J., Vinson, C., Han, J. and Thiel, G. (2005) Regulation of GTP cyclohydrolase I gene transcription by basic region leucine zipper transcription factors. J. Cell. Biochem. 96, 1003-1020
46. Ishii, M., Shimizu, S., Nagai, T., Shiota, K., Kiuchi, Y. and Yamamoto, T. (2001) Stimulation of tetrahydrobiopterin synthesis induced by insulin: possible involvement of phosphatidylinositol 3-kinase. Int. J. Biochem. Cell Biol. 33, 65-73
47. Lapize, C., Pluss, C., Werner, E. R., Huwiler, A. and Pfeilschifter, J. (1998) Protein kinase C phosphorylates and activates GTP cyclohydrolase I in rat renal mesangial cells. Biochem. Biophys. Res. Commun. 251, 802-805
48. Milstien, S., Jaffe, H., Kowlessur, D. and Bonner, T. I. (1996) Purification and cloning of the GTP cyclohydrolase I feedback regulatory protein, GFRP. J. Biol. Chem. 271, 19743-19751
49. Yoneyama, T., Brewer, J. M. and Hatakeyama, K. (1997) GTP cyclohydrolase I feedback regulatory protein is a pentamer of identical subunits. Purification, cDNA cloning, and bacterial expression. J. Biol. Chem. 272, 9690-9696
50. Yoneyama, T. and Hatakeyama, K. (1998) 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. 273, 20102-20108
51. Maita, N., Okada, K., Hirotsu, S., Hatakeyama, K. and Hakoshima, T. (2001) Preparation and crystallization of the stimulatory and inhibitory complexes of GTP cyclohydrolase I and its feedback regulatory protein GFRP. Schizophr. Res. 57, 1153-1156
52. Maita, N., Okada, K., Hatakeyama, K. and Hakoshima, T. (2002) Crystal structure of the stimulatory complex of GTP cyclohydrolase I and its feedback regulatory protein GFRP. Proc. Natl. Acad. Sci. U.S.A. 99, 1212-1217
53. Harada, T., Kagamiyama, H. and Hatakeyama, K. (1993) Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity. Science 260, 1507-1510
54. Maita, N., Hatakeyama, K., Okada, K. and Hakoshima, T. (2004) Structural basis of biopterin-induced inhibition of GTP cyclohydrolase I by GFRP, its feedback regulatory protein. J. Biol. Chem. 279, 51534-51540
55. Ishii, M., Shimizu, S., Wajima, T. et al. (2005) Reduction of GTP cyclohydrolase I feedback regulating protein expression by hydrogen peroxide in vascular endothelial cells. J. Pharmacol. Sci. 97, 299-302
56. Mitchell, B. M., Dorrance, A. M. and Webb, R. C. (2003) GTP cyclohydrolase 1 downregulation contributes to glucocorticoid hypertension in rats. Hypertension 41, 669-674
57. Zheng, J.-S., Yang, X.-Q., Lookingland, K. J. et al. (2003) Gene transfer of human guanosine 5′-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low renin hypertension. Circulation 108, 1238-1245
58. Woo, H. J., Kang, J. Y., Choi, Y. K. and Park, Y. S. (2002) Production of sepiapterin in Escherichia coli by coexpression of cyanobacterial GTP cyclohydrolase I and human 6-pyruvoyltetrahydropterin synthase. Appl. Environ. Microbiol. 68, 3138-3140
59. Krivi, G. G. and Brown, G. M. (1979) Purification and properties of the enzymes from Drosophila melanogaster that catalyze the synthesis of sepiapterin from dihydroneopterin triphosphate. Biochem. Genet. 17, 371-390
60. Zorzi, G., Redweik, U., Trippe, H., Penzien, J. M., Thony, B. and Blau, N. (2002) Detection of sepiapterin in CSF of patients with sepiapterin reductase deficiency. Mol. Genet. Metab. 75, 174-177
61. Abeling, N. G., Duran, M., Bakker, H. D. et al. (2006) Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Mol. Genet. Metab. 89, 116-120
62. Nichol, C. A., Lee, C. L., Edelstein, M. P., Chao, J. Y. and Duch, D. S. (1983) 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. 80, 1546-1550
63. Vasquez-Vivar, J., Duquaine, D., Whitsett, J., Kalyanaraman, B. and Rajagopalan, S. (2002) Altered tetrahydrobiopterin metabolism in atherosclerosis: implications for use of oxidized tetrahydrobiopterin analogues and thiol antioxidants. Arterioscler. Thromb. Vasc. Biol. 22, 1655-1661
64. Tarpey, M. M. (2002) Sepiapterin treatment in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 22, 1519-1521
65. Vasquez-Vivar, J., Whitsett, J., Martasek, P., Hogg, N. and Kalyanaraman, B. (2001) Reaction of tetrahydrobiopterin with superoxide: EPR-kinetic analysis and characterization of the pteridine radical. Free Radical Biol. Med. 31, 975-985
66. Huie, R. E. and Padmaja, S. (1993) The reaction of NO with superoxide. Free Radical Res. Commun. 18, 195-199
67. Milstien, S. and Katusic, Z. (1999) Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function. Biochem. Biophys. Res. Commun. 263, 681-684
68. Laursen, J. B., Somers, M., Kurz, S. et al. (2001) Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 103, 1282-1288
69. Kuzkaya, N., Weissmann, N., Harrison, D. G. and Dikalov, S. (2003) Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J. Biol. Chem. 278, 22546-22554
70. Vasquez-Vivar, J., Martasek, P., Whitsett, J., Joseph, J. and Kalyanaraman, B. (2002) The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study. Biochem. J. 362, 733-739
71. Hauer, C. R., Rebrin, I., Thony, B. et al. (1993) Phenylalanine hydroxylase-stimulating protein/pterin-4α-carbinolamine dehydratase from rat and human liver. Purification, characterization, and complete amino acid sequence. J. Biol. Chem. 268, 4828-4831
72. Davis, M. D., Kaufman, S. and Milstien, S. (1992) Distribution of 4α-hydroxytetrahydropterin dehydratase in rat tissues. Comparison with the aromatic amino acid hydroxylases. FEBS Lett. 302, 73-76
73. Hurshman, A. R., Krebs, C., Edmondson, D. E., Huynh, B. H. and Marletta, M. A. (1999) Formation of a pterin radical in the reaction of the heme domain of inducible nitric oxide synthase with oxygen. Biochemistry 38, 15689-15696
74. Chalupsky, K. and Cai, H. (2005) Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A. 102, 9056-9061
75. Hasegawa, H., Imaizumi, S., Ichiyama, A. et al. (1979) Cofactor activity of diastereoisomers of tetrahydrobiopterin. Chemistry and Biology of Pteridines (Kisliuk, R. L. and Brown, G. M., eds.), pp. 195-200, Elsevier, Amsterdam
76. Matsuura, S., Sugimoto, T., Hasegawa, H., Imaizumi, S. and Ichiyama, A. (1980) Studies on biologically active pteridines. III. The absolute configuration at the C-6 chiral center of tetrahydrobiopterin cofactor and related compounds. J. Biochem. (Tokyo) 87, 951-957
77. Yamamoto, K., Nagano, M., Nakanishi, N. and Hasegawa, H. (1996) A comparison of sepiapterin and tetrahydrobiopterin uptake by RBL2H3 cells. Pteridines 7, 154-156
78. Yamamoto, K., Nakazawa, N. and Hasegawa, H. (1997) Uptake of tetrahydrobiopterin by cells in monolayer cultures of RBL2H3 and PC12 cell lines. Chemistry and Biology of Pteridines and Folates (Pfleiderer, W. and Rokos, H., eds.), pp. 759-763, Blackwell Science, Berlin
79. Hasegawa, H., Yamamoto, K., Matsuhashi, Y., Miyazawa, T., Nakanishi, N. and Oguro, K. (2000) Ability of RBL2H3 cells to lower environmental tetrahydrobiopterin concentration. Pteridines 11, 121-125
80. Hasegawa, H., Yamamoto, K., Sawabe, K. et al. (2001) Cells take up BH4, oxidize it and the oxidized biopterin is preferentially released. Chemistry and Biology of Pteridines and Folates (Milstien, S., Kapatos, G., Levine, R. A. and Shane, B., eds.), pp. 205-210, Kluwer Academic Publishers, Boston
81. Sawabe, K., Yamamoto, K., Matsuhashi, Y. et al. (2003) Increase in the biopterin pool after tetrahydrobiopterin administration is due to uptake of an oxidation product dihydrobiopterin and conversion to the reduced state. Pterins, Folates and Neurotransmitters in Molecular Medicine (Blau, N. and Thony, B., eds.), pp. 41-47, SPS Verlagsgesellschaft, Heilbronn
82. Kobayashi, T., Hasegawa, H., Kaneko, E. and Ichiyama, A. (1991) Gastrointestinal serotonin: depletion due to tetrahydrobiopterin deficiency induced by 2,4-diamino-6-hydroxypyrimidine administration. J. Pharmacol. Exp. Ther. 256, 773-779
83. Kapatos, G., Hirayama, K. and Hasegawa, H. (1992) Tetrahydrobiopterin turnover in cultured rat sympathetic neurons: developmental profile, pharmacologic sensitivity, and relationship to norepinephrine synthesis. J. Neurochem. 59, 2048-2055
84. 2. Pteridines 16, 1-5
85. Sawabe, K., Wakasugi, K. O. and Hasegawa, H. (2004) Tetrahydrobiopterin uptake in supplemental administration: elevation of tissue tetrahydrobiopterin in mice following uptake of the exogenously oxidized product 7,8-dihydrobiopterin and subsequent reduction by an anti-folate-sensitive process. J. Pharmacol. Sci. 96, 124-133
86. Sawabe, K., Suetake, Y., Wakasugi, K. O. and Hasegawa, H. (2005) Accumulated BH4 in mouse liver caused by administration of either 6R- or 6SBH4 consisted solely of the 6R-diastereomer: evidence of oxidation to BH2 and enzymic reduction. Mol. Genet. Metab. 86 (Suppl. 1), S145-S147
87. Sawabe, K., Suetake, Y., Nakanishi, N., Wakasugi, K. O. and Hasegawa, H. (2005) Cellular accumulation of tetrahydrobiopterin following its administration is mediated by two different processes; direct uptake and indirect uptake mediated by a methotrexate-sensitive process. Mol. Genet. Metab. 86 (Suppl. 1), S133-S138
88. Griendling, K. K., Sorescu, D. and Ushio-Fukai, M. (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ. Res. 86, 494-501
89. Schmidt, P. P., Lange, R., Gorren, A. C., Werner, E. R., Mayer, B. and Andersson, K. K. (2001) 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. 6, 151-158
90. Vasquez-Vivar, J., Kalyanaraman, B., Martasek, P. et al. (1998) Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc. Natl. Acad. Sci. U.S.A. 95, 9220-9225
91. Stroes, E., Hijmering, M., van Zandvoort, M., Wever, R., Rabelink, T. J. and van Faassen, E. E. (1998) Origin of superoxide production by endothelial nitric oxide synthase. FEBS Lett. 438, 161-164
92. Vasquez-Vivar, J., Kalyanaraman, B. and Martasek, P. (2003) The role of tetrahydrobiopterin in superoxide generation from eNOS: enzymology and physiological implications. Free Radical Res. 37, 121-127
93. Guzik, T. J., Mussa, S., Gastaldi, D. et al. (2002) Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105, 1656-1662
94. Heitzer, T., Yla-Herttuala, S., Luoma, J. et al. (1996) Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL. Circulation 93, 1346-1353
95. Landmesser, U., Dikalov, S., Price, S. R. et al. (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Invest. 111, 1201-1209
96. Munzel, T., Li, H., Mollnau, H. et al. (2000) 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. 86, E7-E12
97. Maier, W., Cosentino, F., Lutolf, R. B. et al. (2000) Tetrahydrobiopterin improves endothelial function in patients with coronary artery disease. J. Cardiovasc. Pharmacol. 35, 173-178
98. Raman, C. S., Li, H., Martasek, P., Kral, V., Masters, B. S. and Poulos, T. L. (1998) Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Cell 95, 939-950
99. Chen, P. F., Tsai, A. L. and Wu, K. K. (1995) Cysteine 99 of endothelial, nitric oxide synthase (NOS-III) is critical for tetrahydrobiopterin-dependent NOS-III stability and activity. Biochem. Biophys. Res. Commun. 215, 1119-1129
100. Zou, M. H., Shi, C. and Cohen, R. A. (2002) Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J. Clin. Invest. 109, 817-826
101. Tzeng, E., Billiar, T. R., Robbins, P. D., Loftus, M. and Stuehr, D. J. (1995) 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. 92, 11771-11775
102. Wever, R. M. F., van Dam, T., van Rijn, H. J., de Groot, F. and Rabelink, T. J. (1997) Tetrahydrobiopterin regulates superoxide and nitric oxide generation by recombinant endothelial nitric oxide synthase. Biochem. Biophys. Res. Commun. 237, 340-344
103. Reif, A., Frohlich, L. G., Kotsonis, P. et al. (1999) Tetrahydrobiopterin inhibits monomerization and is consumed during catalysis in neuronal NO synthase. J. Biol. Chem. 274, 24921-24929
104. Cai, S., Alp, N. J., McDonald, D., Canevari, L., Heales, S. and Channon, K. M. (2002) GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerization. Cardiovasc. Res. 55, 838-849
105. Meininger, C. J., Marinos, R. S., Hatakeyama, K. et al. (2000) Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. Biochem. J. 349, 353-356
106. 2- imbalance in insulin-resistant rat aorta. Diabetes 48, 2437-2445
107. Shinozaki, K., Nishio, Y., Okamura, T. et al. (2000) Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats. Circ. Res. 87, 566-573
108. Pieper, G. M. (1997) Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J. Cardiovasc. Pharmacol. 29, 8-15
109. Alp, N. J., Mussa, S., Khoo, J. et al. (2003) Tetrahydrobiopterin- dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J. Clin. Invest. 112, 725-735
110. Ceriello, A., Taboga, C., Tonutti, L. et al. (2002) Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation 106, 1211-1218
111. Kawano, H., Motoyama, T., Hirashima, O. et al. (1999) Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J. Am. Coll. Cardiol. 34, 146-154
112. Akbari, C. M., Saouaf, R., Barnhill, D. F., Newman, P. A., LoGerfo, F. W. and Veves, A. (1998) Endothelium-dependent vasodilatation is impaired in both microcirculation and macrocirculation during acute hyperglycemia. J. Vasc. Surg. 28, 687-694
113. Title, L. M., Cummings, P. M., Giddens, K. and Nassar, B. A. (2000) Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E. J. Am. Coll. Cardiol. 36, 2185-2191
114. Ihlemann, N., Rask-Madsen, C., Perner, A. et al. (2003) Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects. Am. J. Physiol. Heart Circ. Physiol. 285, H875-H882
115. Heitzer, T., Brockhoff, C., Mayer, B. et al. (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: evidence for a dysfunctional nitric oxide synthase. Circ. Res. 86, E36-E41
116. Hong, H. J., Hsiao, G., Cheng, T. H. and Yen, M. H. (2001) Supplemention with tetrahydrobiopterin suppresses the development of hypertension in spontaneously hypertensive rats. Hypertension 38, 1044-1048
117. Cosentino, F., Patton, S., d'Uscio, L. V. et al. (1998) Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats. J. Clin. Invest. 101, 1530-1537
118. Kase, H., Hashikabe, Y., Uchida, K., Nakanishi, N. and Hattori, Y. (2005) Supplementation with tetrahydrobiopterin prevents the cardiovascular effects of angiotensin II-induced oxidative and nitrosative stress. J. Hypertens. 23, 1375-1382
119. Taylor, N. E., Maier, K. G., Roman, R. J. and Cowley, Jr, A. W. (2006) NO synthase uncoupling in the kidney of Dahl S rats: role of dihydrobiopterin. Hypertension 48, 1066-1071
120. Khoo, J. P., Nicoli, T., Alp, N. J., Fullerton, J., Flint, J. and Channon, K. M. (2004) Congenic mapping and genotyping of the tetrahydrobiopterin-deficient hph-1 mouse. Mol. Genet. Metab. 82, 251-254
121. Cosentino, F., Barker, J. E., Brand, M. P. et al. (2001) Reactive oxygen species mediate endothelium-dependent relaxations in tetrahydrobiopterin- deficient mice. Arterioscler. Thromb. Vasc. Biol. 21, 496-502
122. Nandi, M., Miller, A., Stidwill, R. et al. (2005) Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse. Circulation 111, 2086-2090
123. Adnot, S., Raffestin, B. and Eddahibi, S. (1995) NO in the lung. Respir. Physiol. 101, 109-120
124. Hampl, V. and Herget, J. (2000) Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension. Physiol. Rev. 80, 1337-1372
125. Steudel, W., Scherrer-Crosbie, M., Bloch, K. D. et al. (1998) Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3. J. Clin. Invest. 101, 2468-2477
126. Fagan, K. A., Fouty, B. W., Tyler, R. C. et al. (1999) The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J. Clin. Invest. 103, 291-299
127. Champion, H. C., Bivalacqua, T. J., Greenberg, S. S., Giles, T. D., Hyman, A. L. and Kadowitz, P. J. (2002) Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 99, 13248-13253
128. Fagan, K. A., Morrissey, B., Fouty, B. W. et al. (2001) Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension. Respir. Res. 2, 306-313
129. Le Cras, T. D. and McMurtry, I. F. (2001) Nitric oxide production in the hypoxic lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L575-L582
130. Brennan, L. A., Steinhorn, R. H., Wedgwood, S. et al. (2003) Increased superoxide generation is associated with pulmonary hypertension in fetal lambs: a role for NADPH oxidase. Circ. Res. 92, 683-691
131. Hoshikawa, Y., Ono, S., Suzuki, S. et al. (2001) Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J. Appl. Physiol. 90, 1299-1306
132. Cracowski, J. L., Cracowski, C., Bessard, G. et al. (2001) Increased lipid peroxidation in patients with pulmonary hypertension. Am. J. Respir. Crit. Care Med. 164, 1038-1042
133. Bowers, R., Cool, C., Murphy, R. C. et al. (2004) Oxidative stress in severe pulmonary hypertension. Am. J. Respir. Crit. Care Med. 169, 764-769
134. Khoo, J. P., Zhao, L., Alp, N. J. et al. (2005) A pivotal role for tetrahydrobiopterin in pulmonary hypertension. Circulation 111, 2126-2133
135. Hattori, Y., Hattori, S., Wang, X., Satoh, H., Nakanishi, N. and Kasai, K. (2007) Oral administration of tetrahydrobiopterin slows the progression of atherosclerosis in apolipoprotein E-knockout mice. Arterioscler. Thromb. Vasc. Biol. 27, 865-870
136. Alp, N. J., McAteer, M. A., Khoo, J., Choudhury, R. P. and Channon, K. M. (2004) Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE-knockout mice. Arterioscler. Thromb. Vasc. Biol. 24, 445-450
137. van Haperen, R., de Waard, M., van Deel, E. et al. (2002) Reduction of blood pressure, plasma cholesterol, and atherosclerosis by elevated endothelial nitric oxide. J. Biol. Chem. 277, 48803-48807
138. d'Uscio, L. V. and Katusic, Z. S. (2006) Increased vascular biosynthesis of tetrahydrobiopterin in apolipoprotein E-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 290, H2466-H2471
139. Stroes, E., Kastelein, J., Cosentino, F. et al. (1997) Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J. Clin. Invest. 99, 41-46
140. Hurlimann, D., Noll, G., Delli Gatti, C. et al. (2005) Oral treatment with tetrahydrobiopterin reverses endothelial dysfunction in oxidative stress in hypercholesterolemia. Circulation 112, II-138
141. Wang, C. H., Li, S. H., Weisel, R. D. et al. (2005) Tetrahydrobiopterin deficiency exaggerates intimal hyperplasia after vascular injury. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R299-R304
142. Ali, Z. A., Alp, N., Tatham, A. L., Greaves, D. R. and Channon, K. M. (2005) Increased endothelial tetrahydrobiopterin synthesis reduces vein graft atherosclerosis in ApoE-knockout mice. Circulation 112, (Suppl. II), 440
143. Celermajer, D. S., Sorensen, K. E., Bull, C., Robinson, J. and Deanfield, J. E. (1994) Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J. Am. Coll. Cardiol. 24, 1468-1474
144. Taddei, S., Virdis, A., Mattei, P. et al. (1995) Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 91, 1981-1987
145. Taddei, S., Galetta, F., Virdis, A. et al. (2000) Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation 101, 2896-2901
146. Eskurza, I., Monahan, K. D., Robinson, J. A. and Seals, D. R. (2004) Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing. J. Physiol. 556, 315-324
147. Eskurza, I., Myerburgh, L. A., Kahn, Z. D. and Seals, D. R. (2005) Tetrahydrobiopterin augments endothelium-dependent dilatation in sedentary but not in habitually exercising older adults. J. Physiol. 568, 1057-1065
148. Higashi, Y., Sasaki, S., Nakagawa, K. et al. (2006) Tetrahydrobiopterin improves aging-related impairment of endothelium-dependent vasodilation through increase in nitric oxide production. Atherosclerosis 186, 390-395
149. Wald, D. S., Law, M. and Morris, J. K. (2002) Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br. Med. J. 325, 1202
150. Bunout, D., Petermann, M., Hirsch, S. et al. (2000) Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls. Nutrition 16, 434-438
151. Verhaar, M. C., Wever, R. M., Kastelein, J. J. et al. (1999) Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation 100, 335-338
152. Hyndman, M. E., Verma, S., Rosenfeld, R. J., Anderson, T. J. and Parsons, H. G. (2002) Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am. J. Physiol. Heart Circ. Physiol. 282, H2167-H2172
153. Doshi, S. N., McDowell, I. F., Moat, S. J. et al. (2002) Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation 105, 22-26
154. Schnyder, G., Roffi, M., Pin, R. et al. (2001) Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N. Engl. J. Med. 345, 1593-1600
155. Toole, J. F., Malinow, M. R., Chambless, L. E. et al. (2004) Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA, J. Am. Med. Assoc. 291, 565-575
156. Bonaa, K. H., Njolstad, I., Ueland, P. M. et al. (2006) Homocysteine lowering and cardiovascular events after acute myocardial infarction. N. Engl. J. Med. 354, 1578-1588
157. Lonn, E., Yusuf, S., Arnold, M. J. et al. (2006) Homocysteine lowering with folic acid and B vitamins in vascular disease. N. Engl. J. Med. 354, 1567-1577
158. Vermeulen, E. G., Stehouwer, C. D., Twisk, J. W. et al. (2000) Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. Lancet 355, 517-522
159. Spijkerman, A. M., Smulders, Y. M., Kostense, P. J. et al. (2005) S-Adenosylmethionine and 5-methyltetrahydrofolate are associated with endothelial function after controlling for confounding by homocysteine: the Hoorn Study. Arterioscler. Thromb. Vasc. Biol. 25, 778-784
160. Stroes, E. S., van Faassen, E. E., Yo, M. et al. (2000) Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ. Res. 86, 1129-1134
161. Antoniades, C., Shirodaria, C., Warrick, N. et al. (2006) 5-Methyl-tetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and eNOS coupling. Circulation 114, 1193-1201
162. Moat, S. J., Clarke, Z. L., Madhavan, A. K., Lewis, M. J. and Lang, D. (2006) Folic acid reverses endothelial dysfunction induced by inhibition of tetrahydrobiopterin biosynthesis. Eur. J. Pharmacol. 530, 250-258
163. Bendall, J. K., Alp, N. J., Warrick, N. et al. (2005) Stoichiometric relationships between endothelial tetrahydrobiopterin, endothelial NO synthase (eNOS) activity, and eNOS coupling in vivo: insights from transgenic mice with endotnelial-targeted GTP cyclohydrolase 1 and eNOS overexpression. Circ. Res. 97, 864-871
164. Heitzer, T., Just, H. and Munzel, T. (1996) Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 94, 6-9
165. Ting, H. H., Timimi, F. K., Haley, E. A., Roddy, M. A., Ganz, P. and Creager, M. A. (1997) Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation 95, 2617-2622
166. Ting, H. H., Timimi, F. K., Boles, K. S., Creager, S. J., Ganz, P. and Creager, M. A. (1996) Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J. Clin. Invest. 97, 22-28
167. Timimi, F. K., Ting, H. H., Haley, E. A., Roddy, M. A., Ganz, P. and Creager, M. A. (1998) Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J. Am. Coll. Cardiol. 31, 552-557
168. Levine, G. N., Frei, B., Koulouris, S. N., Gerhard, M. D., Keaney, J. F. and Vita, J. A. (1996) Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 93, 1107-1113
169. Gokce, N., Keaney, Jr, J. F., Frei, B. et al. (1999) Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 99, 3234-3240
170. Heart Protection Study Group (2002) MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 23-33