Nutrition
Volume 19, Issue 7 , Pages 686-692 , July 2003

Folic acid says NO to vascular diseases

  • Undurti N Das, MD, FAMS

      Affiliations

    • EFA Sciences LLC, Norwood, Massachusetts, USA
    • Corresponding Author InformationCorrespondence to: Undurti N. Das, MD, FAMS, EFA Sciences LLC, 1420 Providence Highway, Suite 266, Norwood, MA 02062, USA.

References 

  1. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042
  2. Quere I, Perneger TV, Zittoun J, et al.  Red blood cell methylfolic acid and plasma homocysteine as risk factors for venous thromboembolism (a matched case-control study). Lancet. 2002;359:747
  3. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease (probable benefits of increasing folic acid intakes). JAMA. 1995;274:1049
  4. De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G. Interaction between hyperhomocystinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost. 2000;26:305
  5. Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem. 1990;1:228
  6. Malinow MR. Hyperhomocyst(e)inemia. A common and easily reversible risk factor for occlusive atherosclerosis. Circulation. 1990;81:2004
  7. Welch GN, Loscalzo J. Mechanism of disease (homocysteine and atherothrombosis). N Engl J Med. 1998;338:1042
  8. Clarke R, Daly L, Robinson K, et al.  Hyperhomocystinemia (an independent risk factor for vascular disease). N Engl J Med. 1991;324:1149
  9. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ. Vitamin B-12, vitamin B-6, and folic acid nutritional status in men with hyperhomocyst(e)inemia. Am J Clin Nutr. 1993;57:47
  10. Quere I, Perneger TV, Zittoun J, et al.  Red blood cell methylfolic acid and plasma homocysteine as risk factors for venous thromboembolism (a matched case-control study). Lancet. 2002;359:747
  11. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest. 1996;98:5
  12. Heinecke JW, Rosen H, Suzuki LA, Chait A. The role of sulfur-containing amino acids in superoxide production and modification of low-density lipoprotein by arterial smooth muscle cells. J Biol Chem. 1987;262:10098
  13. Wall RT, Harlan JM, Harker LA, Striker GE. Homocys(e)ine-induced endothelial cell injury in vitro (a model for the study of vascular injury). Thromb Res. 1986;18:113
  14. Stamler JS, Osborne JA, Jaraki O, et al.  Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest. 1993;91:308
  15. Upchurch GR, Welch GN, Freedman JE, Loscalzo J. Homocys(e)ine attenuates endothelial glutathione peroxidase and thereby potentiates peroxide-mediated cell injury. Circulation. 1995;92:I-228
  16. Tsai J-C, Perrella MA, Yoshizumi M, et al.  Promotion of vascular smooth muscle cell growth by homocyst(e)ine (a link to atherosclerosis). Proc Natl Acad Sci USA. 1994;91:6369
  17. Silverman MD, Tumuluri RJ, Davis M, et al.  Homocysteine upregulates vascular cell adhesion molecule-1 expression in cultured human aortic endothelial cells and enhances monocyte adhesion. Arterioscler Thromb Vasc Biol. 2002;22:587
  18. Holven KB, Aukrust P, Holm T, Ose L, Nenseter MS. Folic acid treatment reduces chemokine release from peripheral blood mononuclear cells in hyperhomocystinemic subjects. Arterioscler Thromb Vasc Biol. 2002;22:699
  19. Friso S, Jacques PF, Wilson PWF, Rosenberg IH, Selhub J. Low circulating vitamin B6 is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation. 2001;103:2788
  20. Das UN. Pyridoxine, thrombosis and prostaglandins. Lancet. 1981;ii:638
  21. Das UN. Hemostatic vitamins and prostaglandins. Med J Austral. 1982;2:316
  22. Das UN. Interaction(s) between essential fatty acids, eicosanoids, cytokines, growth factors, and free radicals (Relevance to new therapeutic strategies in rheumatoid arthritis and other collagen vascular diseases). Prostaglandins Leukot Essent Fatty Acids. 1991;44:201
  23. Li H, Lewis A, Brodsky S, et al.  Homocyateine induces 3-hydroxy-3-methylglutaryl coenzyme A reductase in vascular endothelial cells. Circulation. 2002;105:1037
  24. Bennett-Richards K, Kattenhorn M, Donald A, et al.  Does oral folic acid lower total homocysteine levels and improve endothelial function in children with chronic renal failure. Circulation. 2002;105:1810
  25. Doshi SN, McDowell IF, Moat SJ, et al.  Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation. 2002;105:22
  26. Doshi SN, McDowell IFW, Moat SJ, et al.  Folic acid improves endothelial function in coronary artery disease (an effect mediated by reduction of intracellular superoxide?). Arterioscler Thromb Vasc Biol. 2001;21:1196
  27. Verhaar MC, Wever RM, Kastelein JJ, et al.  5-Methyltetrahydrofolic acid, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation. 1998;97:237
  28. Stroes ES, van Faassen EE, Yo M, et al.  Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res. 2000;86:1129
  29. Gori T, Burstein JM, Ahmed S, et al.  Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance (a human in vivo study). Circulation. 2001;104:1119
  30. Cosentino F, Katusic ZS. Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation. 1995;91:139
  31. Witteveen CF, Giovanelli J, Kaufman S. Reduction of quinonoid dihydrobiopterin to tetrahydrobiopterin by nitric oxide synthase. J Biol Chem. 1996;271:4143
  32. Stroes E, Kastelein J, Cosentino F, et al.  Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest. 1997;99:41
  33. Kaufman S. Some metabolic relationships between biopterin and folic acid (implications for the methyl trap hypothesis). Neurochem Res. 1991;16:1031
  34. Matthews RG, Kaufman S. Characterization of the dihydropterin reductase activity of pig liver methylene tetrahydrofolic acid reductase. J Biol Chem. 1980;255:6014
  35. 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
  36. Kwon NS, Nathan CF, Stuehr DJ. Reduced biopterin as cofactor in the generation of nitrogen oxides by murine macrophages. J Biol Chem. 1989;264:20446
  37. Wermer ER, Wernr-Felmayer G, Wachter H, Mayer B. Biosynthesis of nitric oxide (dependence on pteridine metabolism). Rev Physiol Biochem Pharmacol. 1995;127:97
  38. 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
  39. Kumar KV, Das UN. Are free radicals involved in the pathobiology of human essential hypertension?. Free Radic Biol Med. 1993;19:59
  40. Freeman BA, Crapo JD. Biology of disease (free radicals and tissue injury). Lab Invest. 1982;47:412
  41. 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
  42. Viveros OH, Lee C-L, Abou-Donia MM, Nixon JC, Nichol CA. Biopterin cofactor biosynthesis (independent regulation of GTP cyclohydrolase in adrenal medulla and cortex). Science. 1981;213:349
  43. Komori Y, Hyun J, Chiang K, Fukuto JM. The role of thiols in the apparent activation of rat brain nitric oxide synthase. J Biochem. 1995;117:923
  44. Das UN. Is obesity an inflammatory condition?. Nutrition. 2001;17:953
  45. Mohan IK, Das UN. Oxidant stress, anti-oxidants and nitric oxide in non–insulin dependent diabetes mellitus. Med Sci Res. 1997;25:55
  46. Das UN, Kumar KV, Mohan IK. Lipid peroxides and essential fatty acids in patients with diabetes mellitus and diabetic nephropathy. J Nutr Med. 1994;4:149
  47. Lin Y, Rajala MW, Berger JP, et al.  Hyperglycemia-induced production of acute phase reactants in adipose tissue. J Biol Chem. 2001;276:42077
  48. Guzik TJ, Mussa S, Gastaldi D, et al.  Mechanisms of increased vascular superoxide production in human diabetes mellitus. Circulation. 2002;105:1656
  49. Hong H-J, Hsiao G, Cheng T-H, Yen M-H. Supplementation with tetrahydrobiopterin suppresses the development of hypertension in spontaneously hypertensive rats. Hypertension. 2001;38:1044
  50. Shinozaki K, Hirayama A, Nishio Y, et al.  Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteridine metabolism and vascular oxidative stress. J Am Coll Cardiol. 2001;38:1821
  51. Kanaya S, Ikeda H, Haramaki N, Murohara T, Imaizumi T. Intraplatelet tetrahydrobiopterin plays an important role in regulating canine coronary arterial thrombosis by modulating intraplatelet nitric oxide and superoxide generation. Circulation. 2001;104:2478
  52. Setoguchi S, Mohri M, Shimokawa H, Takeshita A. Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease. J Am Coll Cardiol. 2001;38:493
  53. Walter R, Kaufmann PA, Buck A, et al.  Tetrahydrobiopterin increases myocardial blood flow in healthy volunteers (a double-blind, placebo-controlled study). Swiss Med Wkly. 2001;131:91
  54. Maier W, Cosentino F, Lutolf RB, et al.  Tetrahydrobiopterin improves endothelial function in patients with coronary artery disease. J Cardiovasc Pharmacol. 2000;35:173
  55. Gruhn N, Aldershvile J, Boesgaard S. Tetrahydrobiopterin improves endothelium-dependent vasodilation in nitroglycerin-tolerant rats. Eur J Pharmacol. 2001;416:245
  56. 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
  57. Yu PK, Yu DY, Cringle SJ, Su EN. Tetrahydrobiopterin reverses the impairment of acetylcholine-induced vasodilatation in diabetic ocular microvasculature. J Ocul Pharmacol Ther. 2001;17:123
  58. Prabhakar SS. Tetrahydrobiopterin reverses the inhibition of nitric oxide by high glucose in cultured murine mesangial cells. Am J Physiol Renal Physiol. 2001;281:F179
  59. Johns DG, Dorrance AM, Tramontini NL, Webb RC. Glucocorticoids inhibit tetrahydrobiopterin-dependent endothelial function. Exp Biol Med. 2001;226:27
  60. Meininger CJ, Marinos RS, Hatakeyama K, et al.  Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic rat is due to tetrahydrpbiopterin deficiency. Bichem J. 2000;349(pt 1):353
  61. Tiefenbacher CP, Bleeke T, Vahl C, et al.  Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis. Circulation. 2000;102:2172
  62. Das UN. Is insulin an anti-inflammatory molecule?. Nutrition. 2001;17:409
  63. Das UN. Possible beneficial action(s) of glucose-insulin-potassium regimen in acute myocardial infarction and inflammatory conditions (a hypothesis). Diabetologia. 2000;43:1081
  64. Das UN. Hypothesis (can glucose-insulin-potassium regimen in combination with polyunsaturated fatty acids suppress lupus and other inflammatory conditions?). Prostaglandins Leukot Essent Fatty Acids. 2001;65:109
  65. Guidot DM, Hybertson BM, Kitlowski RP, Repine JE. Inhaled nitric oxide prevents IL-1 induced neutrophil accumulation and associated acute edema in isolated rat lungs. Am J Physiol. 1996;271:1225
  66. Verma S, Dumont AS, Maitland A. Tetrahydrobiopterin attenuates cholesterol induced coronary hyperreactivity to endothelin. Heart. 2001;86:706
  67. Marinos RS, Zhang W, Wu G, Kelly KA, Meininger CJ. Tetrahydrobiopterin levels regulate endothelial cell proliferation. Am J Physiol Heart Circ Physiol. 2001;281:H482
  68. Jiang J, Valen G, Tokuno S, Thoren P, Pernow J. Endothelial dysfunction in atherosclerotic mice (improved relaxation by combined supplementation with l-arginine-tetrahydrobiopterin and enhanced vasoconstriction by endothelin). Br J Pharmacol. 2000;131:1255
  69. Schwartz IF, Schwartz D, Wollman Y, et al.  Tetrahydrobiopterin augments arginine transport in rat cardiac myocytes through modulation of CAT-2 mRNA. J Lab Clin Med. 2001;137:356
  70. Huang A, Vita JA, Venema RC, Keaney JF. Ascorbic acid enhances endothelial nitric oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem. 2000;275:17399
  71. Baker TA, Milstien S, Katusic ZS. Effect of vitamin C on the availability of tetrahydrobiopterin in human endothelial cells. J Cardiovasc Pharmacol. 2001;37:333
  72. Heller R, Unbehaun A, Schellenberg B, et al.  l-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem. 2001;276:40
  73. Tyurin VA, Liu S-X, Tyurina YY, et al.  Elevated levels of S-nitroso albumin in preeclampsia plasma. Circ Res. 2001;88:1210
  74. Sumi-Ichinose C, Urano F, Kuroda R, et al.  Catecholamines and serotonin are differently regulated by tetrahydrobiopterin. A study from 6-pyruvoyltetrahydropterin synthase knockout mice. J Biol Chem. 2001;276:41150
  75. Nakamura K, Bindokas VP, Kowlessur D, et al.  Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons. J Biol Chem. 2001;276:34402
  76. Wiemer G, Itter G, Malinski T, Linz W. Decreased nitric oxide availability in normotensive and hypertensive rats with failing hearts after myocardial infarction. Hypertension. 2001;38:1367
  77. Sun H, Patel KP, Mayhan WG. Tetrahydrobiopterin, a cofactor for NOS, improves endothelial dysfunction during chronic alcohol consumption. Am J Physiol Heart Circ Physiol. 2001;281:H1863
  78. Pita ML, Delgado MJ. Folic acid administration increases N-3 polyunsaturated fatty acids in rat plasma and tissue lipids. Thromb Haemost. 2000;84:420
  79. Durand P, Prost M, Blache D. Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis. 1996;121:231
  80. Andriamampandry M, Freund M, Wiesel ML, et al.  Diets enriched in (n-3) fatty acids affect rat coagulation factors dependent on vitamin K. C R Acad Sci III. 1998;321:415
  81. Mohan IK, Das UN. Prevention of chemically induced diabetes mellitus in experimental animals by polyunsaturated fatty acids. Nutrition. 2001;17:126
  82. Suresh Y, Das UN. Protective action of arachidonic acid against alloxan-induced cytotoxicity and diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids. 2001;64:37
  83. Das UN. Metabolic syndrome X is common in South Asians: but, why and how? Nutrition 2002;18:776
  84. Weisinger HS, Armitage JA, Sinclair AJ, et al.  Perinatal omega-3 deficiency affects blood pressure in later in life. Nat Med. 2001;7:258
  85. Das UN. Can perinatal supplementation of long-chain polyunsaturated fatty acids prevent hypertension in adult life?. Hypertension. 2001;38:E6
  86. Kukor Z, Valent S, Toth M. Regulation of nitric oxide synthase activity by tetrahydrobiopterin in human placentae from normal and pre-eclamptic pregnancies. Placenta. 2000;21:763
  87. Tajima M, Sakagami H. Tetrahydrobiopterin impairs the action of endothelial nitric oxide via superoxide derived from platelets. Br J Pharmacol. 2000;131:958
  88. Bec N, Gorren AFC, Mayer B, et al.  The role of tetrahydrobiopterin in the activation of oxygen by nitric oxide synthase. J Inorg Biochem. 2000;81:207
  89. Choi HJ, Jang YJ, Kim HJ, Hwang O. Tetrahydrobiopterin is released from and causes preferential death of catecholaminergic cells by oxidative stress. Mol Pharmacol. 2000;58:633
  90. Milstein S, Katusic Z. Oxidation of tetrahydrobiopterin by peroxynitrite (implications for vascular endothelial function). Biochem Biophys Res Commun. 1999;263:681
  91. Durand P, Prost M, Blache D. Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity. Arterioscler Thromb Vasc Biol. 1997;17:1939
  92. Das UN. Essential fatty acids (biology and their clinical implications). Asia Pac J Pharmacol. 1991;6:317
  93. Das UN. Essential fatty acids in health and disease. J Assoc Phys India. 1999;47:906
  94. Ishii M, Shimizu S, Nagai T, et al.  Stimulation of tetrahydrobiopterin synthesis induced by insulin (possible involvement of phosphatidyl 3-kinase). Int J Biochem Cell Biol. 2001;33:65
  95. Wald DS, Bishop L, Wald NJ, et al.  Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med. 2001;161:695
  96. Quinlivan EP, McPartlin J, McNulty H, et al.  Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet. 2002;359:227
  97. Lewis CJ, Carne NT, Wilson DB, Yetley EA. Estimated folic acid intakes (data updated to reflect food fortification, increased bioavailability, and dietary supplement use). Am J Clin Nutr. 1999;70:198
  98. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases. Circulation. 1999;99:178
  99. Wald NJ, Law MR, Morris JK, Wald DS. Quantifying the effect of folic acid. Lancet. 2001;358:2069

PII: S0899-9007(02)01044-4

doi: 10.1016/S0899-9007(02)01044-4

Nutrition
Volume 19, Issue 7 , Pages 686-692 , July 2003