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Regulation of tetrahydrobiopterin synthesis and bioavailability in endothelial cells

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Abstract

Tetrahydrobiopterin (BH4) is a member of the pterin family that has a core structure of pyrazino-2,3-d-pyrimidine rings. Because BH4 is an essential cofactor for the biosynthesis of nitric oxide (a major vasodilator), there is growing interest in BH4 biochemistry in endothelial cells (the cells that line blood vessels). BH4 is synthesized via de novo and salvage pathways from guanosine 5′-triphosphate (GTP) and 7,8-dihydrobiopterin, respectively, in animal cells. GTP cyclohydrolase-I (GTP-CH) is the first and rate-controlling enzyme in the de novo pathway. Available evidence shows that endothelial GTP-CH expression and BH4 synthesis are stimulated by a wide array of nutritional (phenylalanine and arginine), hormonal (insulin and estrogen), immunological (inflammatory cytokines including interleukin [IL]-1, interferon-γ, and tumor necrosis factor-α), therapeutic (statins and cyclosporin A), and endothelium-derived (basic fibroblast growth factor and H2O2) factors. In contrast, glucocorticoids and anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor [TGF]-β) inhibit endothelial BH4 synthesis. Because BH4 is oxidized to 7,8-dihydrobiopterin and 7,8-dihydropterin at physiological pH, endothelial BH4 homeostasis is regulated by both BH4 synthesis and its oxidation. Vitamin C, folate, and other antioxidants enhance endothelial BH4 bioavailability through chemical stabilization or scavenging of reactive oxygen species, thereby contributing to the maintenance of physiological homeostasis in the endothelium. New know ledge about the cellular and molecular mechanisms for the regulation of endothelial BH4 synthesis and bioavailability is beneficial for developing effective means to prevent and treat cardiovascular disorders, the leading cause, of death in developed nations.

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References

  1. Hopkins, F. G. (1889) Note on a yellow pigment in butterflies. Nature 40, 335.

    Google Scholar 

  2. Werner-Felmayer, C., Golderer, G., and Werner, E. R. (2002) Tetrahydrobiopterin biosynthesis, utilization and pharmacological effects. Curr. Drug Meta. 3, 159–173.

    CAS  Google Scholar 

  3. Thony, B., Auerbach, G., and Blau N. (2000) Tetrahydrobiopterin biosynthesis, regeneration and function. Biochem. J. 347, 1–16

    PubMed  CAS  Google Scholar 

  4. Wei, C. C., Crane, B. R., and Stuehr, D. J. (2003) Tetrahydrobiopterin radical enzymology. Chem. Rev. 103, 2365–2383.

    PubMed  CAS  Google Scholar 

  5. Kaufman, S. (1993) New tetrahydrobiopterin-dependent systems. Annu. Rev. Nutr. 13, 261–286.

    PubMed  CAS  Google Scholar 

  6. Fitzpatrick, P. F. (1999) Tetrahydrobiopterin-dependen amino acid hydroxylases. Annu. Rev. Biochem. 68, 355–381.

    PubMed  CAS  Google Scholar 

  7. Wei, C. C., Wang, Z. Q., Hemann, C., Hille, R., and Stuehr, D. J. (2003) A tetrahydrobiopterin radical forms and then becomes reduced during Nω-hydroxyarginine oxidation by nitric-oxide synthase. J. Biol. Chem. 278, 46668–46673.

    PubMed  CAS  Google Scholar 

  8. Ignarro, L. J., Cirino, G., Casini, A., and Napoli, C. (1999) Nitric oxide as a signaling molecule in the vascular system: an overview. J. Cardiovasc. Pharmacol 34, 879–886.

    PubMed  CAS  Google Scholar 

  9. Wu, G. and Meininger, C.J. (2000) Arginine nutrition and cardiovascular function. J. Nutr. 130, 2626–2629.

    PubMed  CAS  Google Scholar 

  10. Walter R., Schaffner, A., and Schoedon, G. (2001) Tetrahydrobiopterin in the vascular system. Pteridines 12, 93–120.

    CAS  Google Scholar 

  11. Katusic, Z. S. (2001) Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am. J. Physiol. Heart Circ. Physiol. 281, H981-H986.

    PubMed  CAS  Google Scholar 

  12. Stroes, E., Kastelein, J., Cosentino, F., Erkelens, W., Wever, R., Koomans, H., et al. (1997) Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J. Clin. Invest. 99, 41–46.

    PubMed  CAS  Google Scholar 

  13. Heitzer T., Krohn, K., Albers, S., and Meinertz, T. (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia 43, 1435–1438.

    PubMed  CAS  Google Scholar 

  14. Heitzer, T., Brockhoff, C., Mayer, B., Warnholtz, A., Mollnau, H., Henne, S., et al. (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers. Circ. Res. 86, e36-e41.

    PubMed  CAS  Google Scholar 

  15. Shinozaki, K., Nishio, Y., Okamura, T., Yoshida, Y., Maegawa, H., Kojima, H., 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.

    PubMed  CAS  Google Scholar 

  16. Tiefenbacher, C. P., Bleeke, T., Vahl, C., Amann, K., Vogt, A., and Kubler, W. (2000) Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis. Circulation 102, 2172–2179.

    PubMed  CAS  Google Scholar 

  17. Yamashirom, S., Noguchi, K., Kuniyoshi, Y., Koja, K., and Sakanashi, M. (2003) Role of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts. J. Cardiovasc. Surg. 44, 37–49.

    Google Scholar 

  18. Blau, N., Thony, B., Cotton R. G. H., and Hyland, K. (2001) Disorders of tetrahydrobiopterin and related biogenic amines, in The Metabolic and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D., Childs, B., Kinzler, K. W., et al. eds.), McGraw-Hill Companies Inc., New York, pp. 1725–1776.

    Google Scholar 

  19. Gross, S. S., Jones, C. L., Hattori, Y., and Raman, C. S. (2000) Tetrahydrobiopterin: an essential cofactor of nitric oxide synthase with an elusive role, in Nitric Oxide: Biology and Pathobiology (Ignarro, L. J., ed.), Academic Press, New York, pp. 167–185.

    Google Scholar 

  20. Marinos, R. S., Zhang, W., Wu, G., Kelly, K. A., and Meininger, C. J. (2001) Tetrahydrobiopterin levels regulate endothelial cell proliferation. Am. J. Physiol. Heart Circ. Physiol. 281, H482-H489.

    PubMed  CAS  Google Scholar 

  21. Fisher, D. B. and Kaufman, S. (1973) Tetrahydropterin oxidation without hydroxylation catalyzed by rat liver phenylalanine hydroxylase. J. Biol. Chem. 248, 4300–4304.

    PubMed  CAS  Google Scholar 

  22. Armarego, W. L. F., Randles, D., and Taguchi, H. (1983) Peroxidase catalysed aerobic degradation of 5,6,7,8-tetrahydrobiopterin at physiological pH. Eur. J. Biochem. 135, 393–403.

    PubMed  CAS  Google Scholar 

  23. Davis, M. D., Kaufman, S., and Milstien, S. (1988) The auto-oxidation of tetrahydrobiopterin. Eur. J. Biochem. 173, 345–351.

    PubMed  CAS  Google Scholar 

  24. Milstien, S. and Katusic, Z. (1999) Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function. Biochem. Biophys. Res. Commun. 263, 681–684.

    PubMed  CAS  Google Scholar 

  25. Hamon, C. G., Cutler, P., and Blair, J A. (1989) Tetrahydrobiopterin metabolism in the streptozotocin induced diabetic state in rats. Clin. Chim. Acta 181, 249–254.

    PubMed  CAS  Google Scholar 

  26. Shinozaki, K., Kashiwagi, A., Nishio, Y., Okamura, T., Yoshida, Y., Masada, M., et al. (1999) Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2-imbalance in insulin-resistant rat aorta. Diabetes 48, 2437–2445.

    PubMed  CAS  Google Scholar 

  27. Duch, D. S., Bowers, S. W., Woolf, J. H., and Nichol, C. A. (1984) Biopterin cofactor biosynthesis: GTP cyclohydrolase, neopterin and biopterin in tissues and body fluids of mammalian species. Life Sci. 35, 1895–1901.

    PubMed  CAS  Google Scholar 

  28. Blau, N., Kierat, L., Matasovic, A., Leimbacher, W., Heizmann, C. W., Guardamagna, O., et al. (1994) Antenatal diagnosis of tetrahydrobiopterin deficiency by quantification of pterins in amniotic fluid and enzyme activity in fetal and extrafetal tissue. Clin. Chim. Acta 226, 159–169.

    PubMed  CAS  Google Scholar 

  29. Nixon, J. C., Lee, C. L., Milstien, S., Kaufman, S., and Bartholome, K. (1980) Neopterin and biopterin levels in patients with atypical forms of phenylketonuria. J. Neurochem. 35, 898–904.

    PubMed  CAS  Google Scholar 

  30. Nichol, C. A., Smith, G. K., and Duch, D. S. (1985) Biosynthesis and metabolism of tetrahydrobiopterin and molybdopterin. Annu. Rev. Biochem. 54, 729–764.

    PubMed  CAS  Google Scholar 

  31. Hatakeyama, K., Harada, T., and Kagamiyama, H. (1992) IMP dehydrogenase inhibitors reduce intracellular tetrahydro-biopterin levels through reduction of intracellular GRP level. Indications of the regulation of GRP cyclohydrolase I activity by restriction of GTP availability in the cells. J. Biol. Chem. 267, 20734–20739.

    PubMed  CAS  Google Scholar 

  32. Wu, G., Majumdar, S., Zhang, J., Lee, H., and Meininger, C. J. (1994) Insulin stimulates glycolysis and pentose cycle activity in bovine microvascular endothelial cells. Comp. Biochem. Physiol. 108C, 179–185.

    CAS  Google Scholar 

  33. Wu, G., Haynes, T. E., Hui, H., Yan, W., and Meininger, C. J. (2001) Glutamine metabolism to glucosamine is necessary for glutamine inhibition of endothelial nitric oxide synthesis. Biochem. J. 353, 245–252.

    PubMed  CAS  Google Scholar 

  34. Shin, C. Y., Choi, J. W., Ryu, J. R., Ko, K. H., Choi, J. J., Kim, H. S., et al. (2002) Glucose deprivation decreases nitric oxide production via NADPH depletion in immunostimulated rat primary astrocytes. Glia 37, 268–274.

    PubMed  Google Scholar 

  35. Hatakeyama, K., Harada, T., Suzuki, S., Watanabe, Y., and Kagamiyama, H. (1989) Purification and characterization of rat liver GTP cyclohydrolase I: cooperative binding of GTP to the enzyme. J. Biol. Chem. 264, 21660–21664.

    PubMed  CAS  Google Scholar 

  36. Harada, T., Kagamivama, H., and Hatakeyama, K. (1993) Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity. Science 260, 1507–1510.

    PubMed  CAS  Google Scholar 

  37. Hatakeyama, K., Inoue, Y., Harada, T., and Kagamiyama, H. (1991) Cloning and sequencing of cDNA encoding rat GTP cyclohydrolase I: the first enzyme of the tetrahydrobiopterin biosynthesis pathway. J. Biol. Chem. 266, 765–769.

    PubMed  CAS  Google Scholar 

  38. 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.

    PubMed  CAS  Google Scholar 

  39. 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.

    PubMed  CAS  Google Scholar 

  40. 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. Acta Crystallographica D-Biol. Crystallography 57, 1153–1156.

    CAS  Google Scholar 

  41. 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 97, 3832–3837.

    Google Scholar 

  42. Geller, D. A., Di Silvio, M., Billiar, T. R., and Hatakeyama, K. (2000) GTP cyclohydrolase I is co-induced in hepatocytes stimulated to produce nitric oxide. Biochem. Biophys. Res. Commun. 276, 633–641.

    PubMed  CAS  Google Scholar 

  43. Pastor, C. M., Williams, D., Yoneyama, T., Hatakeyama, K., Singleton, S., Naylor, E., et al. (1996) Competition for tetrahydrobiopterin between phenylalanine hydroxylase and nitric oxide synthase in rat liver. J. Biol. Chem. 271, 24534–24538.

    PubMed  CAS  Google Scholar 

  44. Cai, S., Alp, N. J., McDonald, D. Smith, I., Kay, J., Canevari, L. et al. (2002) GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthese activity, protein levels, and dimerisation. Cardiovasc. Res. 55, 838–849.

    PubMed  CAS  Google Scholar 

  45. Zheng, J. S., Yang, X. G., Lookingland, K. J., Fink, G. D., Hesslinger, C., Kapatos, G., et al. (2003) Gene transfer of human guanosine 5′-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low rennin hypertension. Circulation 108, 1238–1245.

    PubMed  CAS  Google Scholar 

  46. Wu, G. and Meininger, C.J. (1995) Impaired arginine metabolism and NO synthesis in coronary endothelial cells of the spontaneously diabetic BB rats. Am. J. Physiol. Heart Circ. Physiol. 269, H1312-H1318.

    CAS  Google Scholar 

  47. Meininger, C. J., Marinos, R. S., Hatakeyama, K., Martinezzaguilan, R., Rojas, J. D., Kelly, K. A., 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.

    PubMed  CAS  Google Scholar 

  48. Meininger, C. J., Hatakeyama, K., Haynes, T. E., Kelly, K. A., and Wu, G. (2001) Tetrahydrobiopterin deficiency in diabetic rats, in Chemistry and Biology of Pteridines and Folates (Milstien, S., Kapatos, G., Levine, R. A., and Shane, B., eds.), Kluwer Academic Publishers, Boston, MA, pp. 349–353.

    Google Scholar 

  49. Meininger, C. J., Kelly, K. A., Hatakeyama, K., and Wu, G. (2004) Tetrahydrobiopterin deficiency occurs in both type I and type II diabetes mellitus: role of insulin and GTP-CH, in Pterins, Folates, and Neurotransmitters in Molecular Medicine (Blau, N. and Thony, B., eds.), SPS Verlagsgesellschaft mbh, Heilbronn, Germany, pp. 85–89.

    Google Scholar 

  50. Kohli, R., Meininger, C. J., Haynes, T. E., Yan, W., Self, J. T., and Wu, G. (2004) Dietary L-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats. J. Nutr. 134, 600–608.

    PubMed  CAS  Google Scholar 

  51. Meininger, C. J., Cai, S., Parker, J. L., Channon, K. M., Kelly, K. A., Becker, E. J., et al. (2004) GTT cyclohydrolase I gene transfer reverses tetrahydrobiopterin deficiency and increases nitric oxide synthesis in endothelial cells and isolated vessels from diabetic BB rats. FASEB, J., in press.

  52. Alp, N. J., Mussa, S., Khoo, J., Cai, S. J., Guzik, T., Jefferson, A., et al. (2003) Tetrahydro-biopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J. Clin. Invest. 112, 725–735.

    PubMed  CAS  Google Scholar 

  53. Pannirelvam, M., Simon, V., Verma, S., Anderson, T., and Triggle, C. R. (2003) Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small meserteric arteries from diabetic (db/db) mice. Br. J. Pharmacol. 140, 701–706.

    Google Scholar 

  54. Wu, G., Kelly, K. A., Hatakeyama, K., and Meininger, C. J. (2004) Regulation of endothelial tetrahydrobiopterin synthesis by L-arginine, in Pterins, Folates, and Neurotransmitters in Molecular Medicine (Blau, N. and Thony, B., eds.), SPS Verlagsgesellschaft mbh, Heilbronn, Germany, pp. 56–61.

    Google Scholar 

  55. Gesierich, A., Nirromand, F., and Tiefenbacher, C. P. (2002) Role of human GTP cyclohydrolase I and its regulatory protein in tetrahydrobiopterin metabolism. Basic Res. Cardiol. 98, 69–75.

    Google Scholar 

  56. Yoneyama, T. and Hatakeyama, K. (2001) Ligand binding to the inhibitory and stimulatory GTP cyclohydrolase I/GTP cyclohydrolase I feedback regulatory protein complexes. Protein Sci. 10, 871–878.

    PubMed  CAS  Google Scholar 

  57. Werner, E. R., Bahrami, S., Heller, R., and Werner-Felmayer, G. (2002) Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase feedback regulatory protein. J. Biol. Chem. 227, 10129–10133.

    Google Scholar 

  58. Li, H., Meininger, C. J., Hawker, J. R., Haynes, T. E., Kepka-Lenhart, D., Mistry, S. K., et al. (2001) Regulatory role of arginase I and II in nitric oxide, polyamine and proline syntheses in endothelial cells. Am. J. Physiol. 280, E75-E81.

    CAS  Google Scholar 

  59. Arnal, J.-F., Munzel, T., Venema, R. C., James, N. L., Bai, C.-L., Mitch, W. E., et al. (1995) Interactions between L-arginine and L-glutamine change endothelial NO production. J. Clin. Invest. 95, 2565–2572.

    PubMed  CAS  Google Scholar 

  60. Wu, G. and Meininger, C. J. (2002) Regulation of nitric oxide synthesis by dietary factors. Annu. Rev. Nutr. 22, 61–86.

    PubMed  CAS  Google Scholar 

  61. Bagi, Z. and Koller, A. (2003) Lack of nitric oxide mediation of flow-dependent arteriolar dilation in type I diabetes is restored by sepiapterin. J. Vasc. Res. 40, 47–57.

    PubMed  CAS  Google Scholar 

  62. Zeng, G. and Quon, M. (1996) Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J. Clin. Invest. 98, 894–898.

    PubMed  CAS  Google Scholar 

  63. Verma, S., Arikawa, E., Yao, L., Laher, I., and McNeill, J. H. (1998) Insulin-induced vasodilation is dependent on tetrahydrobiopterin synthesis. Metabolism 47, 1037–1039

    PubMed  CAS  Google Scholar 

  64. Ishii, M., Shimizu, S., Nagai, T., Kiuchi, Y., and Yamamoto, T. (1999) Insulin stimulates tetrahydrobiopterin synthesis in mouse brain microvascular endothelial cells. Pteridines 10, 213–216.

    CAS  Google Scholar 

  65. 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.

    PubMed  CAS  Google Scholar 

  66. Saruta, T. (1996) Mechanism of glucocorticoid-induced hypertension. Hypertens. Res. 19, 1–8.

    PubMed  CAS  Google Scholar 

  67. Mitchell, B. M. and Webb, R. C. (2002) Impaired vasodilation and nitric oxide synthase activity in glucocorticoid-induced hypertension. Biol. Res. Nurs. 4, 16–21.

    PubMed  Google Scholar 

  68. Simmons, W. W., Ungureanu-Longrois, D., Smith, G. K., Smith, T. W., and Kelly, R. A. (1996) Glucocorticoids regulate inducible nitric oxide synthase by inhibiting tetrahydro-biopterin synthesis and L-arginine transport. J. Biol. Chem. 271, 23928–23937.

    PubMed  CAS  Google Scholar 

  69. Johns, D. G., Dorrance, A. M., Tramontini, N. L., and Webb, R. C. (2001) Glucocorticoids inhibit tetrahydrobiopterin-dependent endothelial function. Exp. Biol. Med. 226, 27–31.

    CAS  Google Scholar 

  70. Holm, P., Korsgaard, P., Shalmi, M., Andersen, H. L., Hougaard, P., Skouby, S. O., et al. (1997) Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits. J. Clin. Invest. 100, 821–828.

    PubMed  CAS  Google Scholar 

  71. MacRitchie, A. N., Jun, S. S., Chen, Z., German, Z., Yuhanna, I. S., et al. (1997) Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ. Res. 81, 355–362.

    PubMed  CAS  Google Scholar 

  72. Shiota, K., Ishii, M., Yamamoto, T., Shimizu, S., and Kiuchi, Y. (2000) Stimulation of tetrahydrobiopterin synthesis by 17(-estradiol in brain microvascular endothelial cells. Pteridines 11, 129–132.

    CAS  Google Scholar 

  73. Gonzales, R. J., Walker, B. R., and Kanagy, N. L. (2001) 17 beta-estradiol increases nitric oxide-dependent dilation in rat pulmonary, arteries and thoracic aorta. Am. J. Physiol. Lung Cell Mol. Physiol. 280, L555-L564.

    PubMed  CAS  Google Scholar 

  74. Werner, E. R., Werner-Felmayer, G., and Mayer, B. (1998) Tetrahydrobiopterin, cytokines, and nitric oxide synthesis. Proc. Soc. Exp. Biol. Med. 219, 171–182.

    PubMed  CAS  Google Scholar 

  75. Schoedon, G., Schneemann, M., Blau, N., Edgell, C.-J. S., and Chaffner, A. (1993) Modulation of human endothelial cell tetrahydrobiopterin synthesis by activating and deactivating cytokines: new perspectives on endothelium-derived relaxing factor. Biochem. Biophys. Res. Comm. 196, 1343–1348.

    PubMed  CAS  Google Scholar 

  76. Rosenkranz-Weiss, P., Sessa, W. C., Milstien, S., Kaufman, S., Watson, C. A., and Pober, J. S. (1994) Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. J. Clin. Invest. 93, 2236–2243.

    Article  PubMed  CAS  Google Scholar 

  77. Walter, R., Schaffner, A., Blau, N., Kierat, L., and Schoedon, G. (1994) Tetrahydrobiopterin is a secretory product of murine vascular endothelial cells. Biochem. Biophys. Res. Comm. 203, 1522–1526.

    PubMed  CAS  Google Scholar 

  78. Wolin, M. S. (2000) Mechanisms through which reactive nitrogen and oxygen species interact with physiological signaling systems, in Nitric Oxide: Biology and Pathobiology (Ignarro, L. J., ed.), Academic Press, New York, NY, pp. 277–292.

    Google Scholar 

  79. Shimizu, S., Ishii, M., Kawakami, Y., Momose, K., and Yamamoto, T. (1998) Protective effects of tetrahydrobiopterin against nitric oxide-induced endothelial cell death. Life Sci. 63, 1585–1592.

    PubMed  CAS  Google Scholar 

  80. Hattori, Y., Nakanishi, N., Kasai, K., and Shimoda, S. (1997) GTP cyclohydrolase I mRNA induction and tetrahydrobiopterin synthesis in human endothelial cells. Biochim. Biophys. Acta 1358, 61–66.

    PubMed  CAS  Google Scholar 

  81. Werner-Felmayer, G., Werner, E. R., Fuchs, D., Hausen, A., Reibnegger, G., Schmidt, K., et al. (1993) Pteridine biosynthesis in human endothelial cells: impact on nitric oxide-mediated formation of cyclic GMP. J. Biol. Chem. 268, 1842–1846.

    PubMed  CAS  Google Scholar 

  82. 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.

    PubMed  CAS  Google Scholar 

  83. Hattori, Y., Nakanishi, N., Kasai, K., and Shimoda, S. (1997) GTP cyclohydrolase I mRNA induction and tetrahydrobiopterin synthesis in human endothelial cells. Biochim. Biophys. Acta. 1358, 61–66.

    PubMed  CAS  Google Scholar 

  84. Walter, R., Linscheid, P., Blau, N., Kierat, L., Schaffner, A., and Schoedon, G. (1998) Induction of tetrahydrobiopterin synthesis in human umbilical Vein smooth muscle cells by inflammatory stimuli. Immunol. Lett. 60, 13–17.

    PubMed  CAS  Google Scholar 

  85. Andert, S. E., Griesmacher, A., Zuckermann, A., and Muller, M. M. (1992) Neopterin release from human endothelial-cells is triggered by interferon-gamma. Clin. Exp Immunol. 88, 555–558.

    Article  PubMed  CAS  Google Scholar 

  86. Linscheid, P., Schaffner, A., Blau, N., and Schoedon, G. (1998) Regulation of 6-pyruvoyl-tetrahydroptein synthase activity and messenger RNA abundance in human vascular endothelial cells. Circulation 98, 1703–1706.

    PubMed  CAS  Google Scholar 

  87. Franscini, N., Blau, N., Walter, R. B., Schaffner, A., and Schoedon, G. (2003) Critical role of interleukin-1 beta for transcriptional regulation of endothelia 6-pyruvoyltetrahydropterin synthase. Arterioscler. Thromb. Vas. Biol. 23, E50-E53.

    Google Scholar 

  88. Wei, L. H., Jacobs, A. T., Morris, S. M., and Ignarro, L. J. (2000) IL-4 and IL-13 upregulate arginase I expression by cAMP and JAK/Stat6 pathways in vascular smooth muscle cells. Am. J. Physiol. Cell Physiol. 279, C248-C256.

    PubMed  CAS  Google Scholar 

  89. Endres, M., Laufs, U., Huang, Z. H., Nakamura, T., Huang, P., Moskowitz, M. A., et al. (1998) Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. U S A 95, 8880–8885.

    PubMed  CAS  Google Scholar 

  90. Hattori, Y., Nakanishi, N., Akimoto, K., Yoshida, M., and Kasai K. (2003) HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 23, 176–182.

    PubMed  CAS  Google Scholar 

  91. Rubin, A. M., and Kang, H. (1987) Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology 37, 1072–1076.

    PubMed  CAS  Google Scholar 

  92. Ishii, M., Shimizu, S., Shiota, K., Yamamoto, S., Kiuchi, Y., and Yamamoto, T. (2002) Stimulation of tetrahydrobiopterin synthesis by cyclosporin A in mouse brain microvascular endothelial cells. Int. J. Biochem. Cell Biol. 34, 1134–1141.

    PubMed  CAS  Google Scholar 

  93. Ishii, M., Shimizu, S., Shiota, K., Yamamoto, S., Kiuchi, Y., and Yamamoto, T. (2002) Stimulation of tetrahydrobiopterin synthesis by cyclosporine A during lipopolysaccharide treatment in vascular endothelial cells. Pteridines 13, 89–93.

    CAS  Google Scholar 

  94. Matoba, T., Shimokawa, H., Nakashima, M., Hirakawa, Y., Mukai, Y., Hirano, K., et al. (2000) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J. Clin. Invest. 106, 1521–1530.

    PubMed  CAS  Google Scholar 

  95. Shimizu, S., Shiota, K., Yamamoto, S., Miyasaka, Y., Ishii, M., Watabe, T., et al. (2003) Hydrogen peroxide stimulates tetrahydrobiopterin synthesis through the induction of GTP-cyclohydrolase I and increases nitric oxide synthase activity in vascular endothelial cells. Free Rad. Biol. Med. 34, 1343–1352.

    PubMed  CAS  Google Scholar 

  96. Shiota, K., Shimizu, S., Ishii, M., Yamamoto, S., Iwasaki, M., Yamamoto, T., et al. (2002) Hydrogen peroxide stimulates the LPs-induced tetrahydrobiopterin synthesis in mouse brain microvascular endothelial cells. Pteridimes 13, 21–25.

    CAS  Google Scholar 

  97. Wu, H. M., Yuan, Y., McCarthy, M., and Granger, H. J. (1996) Acidic and basic FGFs dilate arterioles of skeletal muscle through a NO-dependent mechanism. Am. J. Physiol. Heart Circ. Physiol. 40, H1087-H1093.

    Google Scholar 

  98. Shimizu, S., Miyasaka, Y., Yamamoto, S., Ishii, M., and Kiuchi, Y. (2003) Stimulation of tetrahydrobioptenin synthesis by basic fibroblast growth factor in vascular endothelial cells. Pteridines 14, 9–12.

    CAS  Google Scholar 

  99. Dhillon, B., Badiwala, M. V., Maitland, A., Rao, V., Li, S. H., and Verma, S. (2003) Tetrahydrobiopterin attenuates homocysteine induced endothelial dysfunction. Mol. Cell. Biochem. 247, 223–227.

    PubMed  CAS  Google Scholar 

  100. Fiege, B., Ballhausen, D., Kierat, L., Leimbacher, W., Goriounov, D., Schircks, B., et al. (2004) Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration. Mol. Genet. Metab. 81, 45–51.

    PubMed  CAS  Google Scholar 

  101. Tsutsui, M., Milstien, S., and Katusic, Z. S. (1996) Effect of tetrahydrobiopterin on endothelial function in canine middle cerebral arteries. Circ. Res. 79, 336–342.

    PubMed  CAS  Google Scholar 

  102. Kirsch, M., Korth, H. G., Stenert, V., Sustmann, R., and de Groot, H. (2003) The autoxidation of tetrahydrobiopterin revisited—proof of superoxide formation from reaction of tetrahydrobiopterin with molecular oxygen. J. Biol. Chem. 278, 24481–24490.

    PubMed  CAS  Google Scholar 

  103. 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.

    PubMed  CAS  Google Scholar 

  104. Yang, D., Levens, N., Zhang, J. N., Vanhoutte, P. M., and Feletou, M. (2003) Specific potentiation of endothelium-dependent contractions in SHR by tetrahydrobiopterin. Hypertension 41, 136–142.

    PubMed  CAS  Google Scholar 

  105. Ihlemann, N., Rask-Madsen, C., Perner, A., Dominguez, H., Hermann, T., Kober, L., 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.

    PubMed  CAS  Google Scholar 

  106. Fukushima, T. and Nixon, J. C. (1980) Analysis of reduced forms of biopterin in biological tissues and fluids. Anal. Biochem. 102, 176–188.

    PubMed  CAS  Google Scholar 

  107. Shinozaki, K., Hirayama, A., Nishio, Y., Yoshida, Y., Ohtani, T., Okamura, T., et al. (2001) Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteridine metabolism and vascular oxidative stress. J. Am. Coll. Cardiol. 38, 1821–1828.

    PubMed  CAS  Google Scholar 

  108. Kapatos, G. (1990) Tetrahydrobiopterin synthesis rate and turnover time in neuronal cultures from embryonic rat mesencephalon and hypothalamus. J. Neurochem. 55, 129–136.

    PubMed  CAS  Google Scholar 

  109. 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.

    Article  PubMed  CAS  Google Scholar 

  110. Das, U. N. (2003) Folic acid says NO to vascular diseases. Nutrition 19, 686–692.

    PubMed  CAS  Google Scholar 

  111. Huang, A., Vita, J. A., Vnema, R. C., and Keaney, J. F. (2000) Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J. Biol. Chem. 275, 17399–17406.

    PubMed  CAS  Google Scholar 

  112. Heller, R., Unbehaun, A., Schellenberg, B., Mayer, B., Werner-Felmayer, G., and Werner, E. R. (2001) L-ascorbic acid potentiates endothelia nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J. Biol. Chem. 276, 40–47.

    PubMed  CAS  Google Scholar 

  113. d'Uscio, L. V., Milstien, S., Richardson, D., Smith, L., and Katusic, Z. S. (2003) Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ. Res. 92, 88–95.

    PubMed  Google Scholar 

  114. 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.

    PubMed  CAS  Google Scholar 

  115. Fang, Y. Z., Yang, S., and Wu, G. (2002) Free radicals, antioxidants, and nutrition. Nutrition 18, 872–879.

    PubMed  CAS  Google Scholar 

  116. Rezk, B. M., Haenen, G. R. M. M., van der Vijgh, W. J. F., and Bast, A. (2003) Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. FEBS Lett. 555, 601–605.

    PubMed  CAS  Google Scholar 

  117. Reiter, R. and Tan, D. X. (2002) Melatonin: an antioxidant in edible plants. Ann. N.Y. Acad. Sci. 957, 341–344.

    Article  PubMed  CAS  Google Scholar 

  118. Quyyumi, A. A. (1998) Does acute improvement of endothelial dysfunction in coronary artery disease improve myocardial ischemia? A double-blind comparison of parenteral D-and L-arginine. J. Am. Coll. Cardiol. 32, 904–911.

    PubMed  CAS  Google Scholar 

  119. Ruiz, E. and Tejerina, T. (1998) Relaxant effects of L-citrulline in rabbit vascular smooth muscle. Br. J. Pharmacol. 125, 186–192.

    PubMed  CAS  Google Scholar 

  120. Wu, G., Fang, Y. Z., Yang, S., Lupton, J. R., and Turner, N. D. (2004) Glutathione metabolism and its implications for health. J. Nutr. 134, 489–492.

    PubMed  CAS  Google Scholar 

  121. Komori, Y., Hyun, J. J., Chiang, K., and Fukuto, J. M. (1995) The role of thiols in the apparent activation of rat-brain nitric-oxide synthase (NOS), J. Biochem. 117, 923–927.

    PubMed  CAS  Google Scholar 

  122. Ghigo, D., Alessio, P., Foco, A., Bussolino, F., Costamagna, C., Heller, R., et al. (1993) Nitric-oxide synthesis is impaired in glutathione-depleted human umbilical vein endothelial-cells. Am. J. Physiol. 265, C728-C732.

    PubMed  CAS  Google Scholar 

  123. Tachi, Y., Okuda, Y., Bannai, C., Bannai, S., Shinohara, M., Shimpuu, H., et al. (2001) Hyperglycemia in diabetic rats reduces the glutathione content in the aortic tissue. Life Sci. 69, 1039–1047.

    PubMed  CAS  Google Scholar 

  124. Ganafa, A. A., Socci, R. R., Eatman, D., Silvestrova, N., Abukhalaf, I. K., and Bayorh, M. A. (2002) Acute inhibiition of glutathione biosynthesis alters endothelial function and blood pressure in rats. Eur. J. Pharmacol. 454, 217–223.

    PubMed  CAS  Google Scholar 

  125. Gilmont, R. R., Dardano, A., Young, M., Engle, J. S., Adamson, B. S., Smith, D. J., et al. (1998) Effects of glutathione depletion on oxidant-induced endothelial cell injury. J. Surg. Res. 80, 62–68.

    PubMed  CAS  Google Scholar 

  126. Bleeke, T., Zhang, H., Madamanchi, N., Patterson, C., and Faber, J. E. (2004) Catecholamine-induced vascular wall growth is dependent on generation of reactive oxygen species. Circ. Res. 94, 37–45.

    PubMed  CAS  Google Scholar 

  127. Barzilai, A., Melamed, E., and Shirvan, A. (2001) Is there a rationale for neuroprotection against dopamine toxicity in Parkinson's disease? Cell. Mol. Neurobiol. 21, 215–235.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Nutrition and Department of Animal Science, Texas A&M University, 77843, College Station, TX

    Wenjuan Shi, Tony E. Haynes & Guoyao Wu

  2. Department of Medical Physiology and Cardiovascular Research Institute, The Texas A&M University System Health Science Center, 77843, College Station, TX

    Cynthia J. Meininger & Guoyao Wu

  3. Department of Surgery, University of Pittsburgh, 15213, Pittsburgh, PA

    Kazuyuki Hatakeyama

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  1. Wenjuan Shi
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Correspondence to Guoyao Wu.

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Shi, W., Meininger, C.J., Haynes, T.E. et al. Regulation of tetrahydrobiopterin synthesis and bioavailability in endothelial cells. Cell Biochem Biophys 41, 415–433 (2004). https://doi.org/10.1385/CBB:41:3:415

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