Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease

American Journal of Physiology - Heart and Circulatory Physiology

Volumn 294, Issue 5, 2008, Pages

  Moens, An L ^a,b,c   Vrints, Christiaan J ^b   Claeys, Marc J ^b   Timmermans, Jean Pierre ^b   Champion, Hunter C ^a   Kass, David A ^a  

^a DEPARTMENT OF PATHOLOGY   (United States)

^b UNIVERSITY OF ANTWERP   (Belgium)

^c ANTWERP UNIVERSITY HOSPITAL   (Belgium)

Author keywords

Endothelial nitric oxide synthase; Homocysteine; Superoxide; Tetrahydrobiopterin; Uncoupling

Indexed keywords

CARBAMAZEPINE; CYANOCOBALAMIN; ENDOTHELIAL NITRIC OXIDE SYNTHASE; FOLIC ACID; HOMOCYSTEINE; PYRIDOXINE; TETRAHYDROBIOPTERIN; VALPROIC ACID; CARDIOVASCULAR AGENT; NITRIC OXIDE;

ANTIOXIDANT ACTIVITY; ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CONGENITAL HEART MALFORMATION; DRUG EFFECT; DRUG MECHANISM; DRUG MEGADOSE; HUMAN; LOW DRUG DOSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW; ANIMAL; HEMODYNAMICS; METABOLISM; MORTALITY; PATHOPHYSIOLOGY; VASCULAR ENDOTHELIUM;

ANIMALS; ATHEROSCLEROSIS; CARDIOVASCULAR AGENTS; CARDIOVASCULAR DISEASES; ENDOTHELIUM, VASCULAR; FOLIC ACID; HEART DEFECTS, CONGENITAL; HEMODYNAMICS; HOMOCYSTEINE; HUMANS; NITRIC OXIDE; NITRIC OXIDE SYNTHASE TYPE III;

EID: 44949141630     PISSN: 03636135     EISSN: 15221539     Source Type: Journal    
DOI: 10.1152/ajpheart.91503.2007     Document Type: Review

References (101)

1. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev 55: 145-149, 1997.
2. Apeland T, Mansoor MA, Pentieva K, McNulty H, Seljeflot I, Strandjord RE. The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic drugs. Epilepsy Res 51: 237-247, 2002.
3. B-Vitamin Treatment Trialists' Collaboration. Homocysteine- lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J 151: 282-287, 2006.
4. Bailey LB, Berry RJ. Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr 81: 1213S-1217S, 2005.
5. Bayston R, Russell A, Wald NJ, Hoffbrand AV. Folic acid fortification and cancer risk. Lancet 370: 2004, 2007.
6. Bellamy MF, McDowell IF, Ramsey MW, Brownlee M, Newcombe RG, Lewis MJ. Oral folate enhances endothelial function in hyperhomocysteinaemic subjects. Eur J Clin Invest 29: 659-662, 1999.
7. Boneva RS, Botto LD, Moore CA, Yang Q, Correa A, Erickson JD. Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979-1997. Circulation 103: 2376-2381, 2001.
8. Botto LD, Mulinare J, Erickson JD. Occurrence of congenital heart defects in relation to maternal multivitamin use. Am J Epidemiol 151: 878-884, 2000.
9. 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 274: 1049-1057, 1995.
10. Campbell NR. How safe are folic acid supplements? Arch Intern Med 156: 1638-1644, 1996.
11. Carnicer R, Navarro MA, Arbones-Mainar JM, Acin S, Guzman MA, Surra JC, Arnal C, de Las Heras M, Blanco-Vaca F, Osada J. Folic acid supplementation delays atherosclerotic lesion development in apoE-deficient mice. Life Sci 80: 638-643, 2007.
12. Chambers JC, Ueland PM, Obeid OA, Wrigley J, Refsum H, Kooner JS. Improved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteine. Circulation 102: 2479-2483, 2000.
13. Chao CL, Chien KL, Lee YT. Effect of short-term vitamin (folic acid, vitamins B6 and B12) administration on endothelial dysfunction induced by post-methionine load hyperhomocysteinemia. Am J Cardiol 84: 1359-1361, 1999.
14. Chasan-Taber L, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tishler PV, Willett W, Hennekens CH, Stampfer MJ. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 15: 136-143, 1996.
15. Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr 130: 129-132, 2000.
16. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 324: 1149-1155, 1991.
17. Cosentino F, Katusic ZS. Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation 91: 139-144, 1995.
18. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA 274: 1698-1702, 1995.
19. De Vriese AS, Van d V, Blom HJ, Vanhoutte PM, Verbeke M, Lameire NH. The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin-induced diabetic rats is restored by 5-methyltetrahydrofolate. Diabetologia 43: 1116-1125, 2000.
20. Doshi SN, McDowell IF, Moat SJ, Lang D, Newcombe RG, Kredan MB, Lewis MJ, Goodfellow J. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol 21: 1196-1202, 2001.
21. Durand P, Lussier-Cacan S, Blache D. Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J 11: 1157-1168, 1997.
22. 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 121: 231-243, 1996.
23. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 131: 363-375, 1999.
24. Finkelstein JD, Kyle W, Harris BJ. Methionine metabolism in mammals. Regulation of homocysteine methyltransferases in rat tissue. Arch Biochem Biophys 146: 84-92, 1971.
25. Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, Hess DL, Davis CE. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 98: 204-210, 1998.
26. Ford ES, Byers TE, Giles WH. Serum folate and chronic disease risk: findings from a cohort of United States adults. Int J Epidemiol 27: 592-598, 1998.
27. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10: 111-113, 1995.
28. Gallagher PM, Meleady R, Shields DC, Tan KS, McMaster D, Rozen R, Evans A, Graham IM, Whitehead AS. Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation. Circulation 94: 2154-2158, 1996.
29. Giles WH, Kittner SJ, Anda RF, Croft JB, Casper ML. Serum folate and risk for ischemic stroke. First National Health and Nutrition Examination Survey epidemiologic follow-up study. Stroke 26: 1166-1170, 1995.
30. Gori T, Burstein JM, Ahmed S, Miner SE, Al Hesayen A, Kelly S, Parker JD. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation 104: 1119-1123, 2001.
31. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 354: 407-413, 1999.
32. Harpel PC, Zhang X, Borth W. Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. J Nutr 126: 1285S-1289S, 1996.
33. 2+-/calmodulin-dependent formation of hydrogen peroxide by brain nitric oxide synthase. Biochem J 281: 627-630, 1992.
34. Henning SM, Swendseid ME, Ivandic BT, Liao F. Vitamins C, E and A and heme oxygenase in rats fed methyl/folate-deficient diets. Free Radic Biol Med 23: 936-942, 1997.
35. Hjemdahl P. Smoking, nicotine and thrombotic risk - a role for platelet dependent thrombin generation? Eur Heart J 22: 16-18, 2001.
36. Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 316: 894-898, 1998.
37. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288: 2015-2022, 2002.
38. Hyndman ME, Verma S, Rosenfeld RJ, Anderson TJ, Parsons HG. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol 282: H2167-H2172, 2002.
39. Kamen B. Folate and antifolate pharmacology. Semin Oncol 24: S18-30-S18-39, 1997.
40. Kang SS, Passen EL, Ruggie N, Wong PW, Sora H. Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation 88: 1463-1469, 1993.
41. Kaufman S. Some metabolic relationships between biopterin and folate: implications for the "methyl trap hypothesis". Neurochem Res 16: 1031-1036, 1991.
42. Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 65: 1790-1795, 1997.
43. Khajuria A, Houston DS. Induction of monocyte tissue factor expression by homocysteine: a possible mechanism for thrombosis. Blood 96: 966-972, 2000.
44. Kim YI. Will mandatory folic acid fortification prevent or promote cancer? Am J Clin Nutr 80: 1123-1128, 2004.
45. Kinoshita H, Tsutsui M, Milstien S, Katusic ZS. Tetrahydrobiopterin, nitric oxide and regulation of cerebral arterial tone. Prog Neurobiol 52: 295-302, 1997.
46. Kluijtmans LA, Kastelein JJ, Lindemans J, Boers GH, Heil SG, Bruschke AV, Jukema JW, van den Heuvel LP, Trijbels FJ, Boerma GJ, Verheugt FW, Willems F, Blom HJ. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation 96: 2573-2577, 1997.
47. Kuch B, Bobak M, Fobker M, Junker R, von Eckardstein A, Marmot M, Hense HW. Associations between homocysteine and coagulation factors - a cross-sectional study in two populations of central Europe. Thromb Res 103: 265-273, 2001.
48. Landewe RB, van den Borne BE, Breedveld FC, Dijkmans BA. Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity. Lancet 355: 1616-1617, 2000.
49. Lange H, Suryapranata H, De LG, Borner C, Dille J, Kallmayer K, Pasalary MN, Scherer E, Dambrink JH. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 350: 2673-2681, 2004.
50. Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 88: 1906-1914, 1991.
51. Loria CM, Ingram DD, Feldman JJ, Wright JD, Madans JH. Serum folate and cardiovascular disease mortality among US men and women. Arch Intern Med 160: 3258-3262, 2000.
52. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 98: 5-7, 1996.
53. Loscalzo J. Homocysteine trials - clear outcomes for complex reasons. N Engl J Med 354: 1629-1632, 2006.
54. Mangoni AA, Arya R, Ford E, Asonganyi B, Sherwood RA, Ouldred E, Swift CG, Jackson SH. Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial. Thromb Res 110: 13-17, 2003.
55. Mangoni AA, Sherwood RA, Swift CG, Jackson SH. Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med 252: 497-503, 2002.
56. Manzoor M, Runcie J. Folate-responsive neuropathy: report of 10 cases. Br Med J 1: 1176-1178, 1976.
57. Massy ZA. Reversal of hyperhomocyst(e)inaemia in chronic renal failure-is folic or folinic acid the answer? Nephrol Dial Transplant 14: 2810-2812, 1999.
58. Midorikawa S, Sanada H, Hashimoto S, Watanabe T. Enhancement by homocysteine of plasminogen activator inhibitor-1 gene expression and secretion from vascular endothelial and smooth muscle cells. Biochem Biophys Res Commun 272: 182-185, 2000.
59. Moat SJ, Madhavan A, Taylor SY, Payne N, Allen RH, Stabler SP, Goodfellow J, McDowell IF, Lewis MJ, Lang D. High- but not low-dose folic acid improves endothelial function in coronary artery disease. Eur J Clin Invest 36: 850-859, 2006.
60. Moens AL, Champion HC, Claeys MJ, Tavazzi B, Kaminski PM, Wolin MS, Borgonjon DJ, Van Nassauw L, Haile A, Zviman M, Bedja D, Wuyts FL, Elsaesser RS, Cos P, Gabrielson KL, Lazzarino G, Paolocci N, Timmermans JP, Vrints CJ, Kass DA. High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury. Circulation. In press.
61. Moens AL, Claeys MJ, Wuyts FL, Goovaerts I, Van Hertbruggen E, Wendelen LC, Van Hoof VO, Vrints CJ. Effect of folic acid on endothelial function following acute myocardial infarction. Am J Cardiol 99: 476-481, 2007.
62. Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation 95: 2032-2036, 1997.
63. Morrison HI, Schaubel D, Desmeules M, Wigle DT. Serum folate and risk of fatal coronary heart disease. JAMA 275: 1893-1896, 1996.
64. Nachmany A, Gold V, Tsur A, Arad D, Weil M. Neural tube closure depends on nitric oxide synthase activity. J Neurochem 96: 247-253, 2006.
65. National Academy of Sciences. Dietary Reference Intakes: Folate, Other B-vitamins and Choline. Washington, DC: National Academy Press, 2000.
66. O'Grady HL, Leahy A, McCormick PH, Fitzgerald P, Kelly CK, Bouchier-Hayes DJ. Oral folic acid improves endothelial dysfunction in cigarette smokers. J Surg Res 106: 342-345, 2002.
67. Oster K. Atherosclerosis treated with folic acid (Abstract). Federation Proceedings 40: 865, 1981.
68. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 49: 31-62, 1998.
69. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101: 1899-1906, 2000.
70. Schalhorn A, Kuhl M. Clinical pharmacokinetics of fluorouracil and folinic acid. Semin Oncol 19: 82-92, 1992.
71. Schnyder G, Pin R, Roffi M, Flammer Y, Hess OM. Association of plasma homocysteine with the number of major coronary arteries severely narrowed. Am J Cardiol 88: 1027-1030, 2001.
72. Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, Meier B, Turi ZG, Hess OM. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 345: 1593-1600, 2001.
73. Scott J, Weir D. Folate/vitamin B12 inter-relationships. Essays Biochem 28: 63-72, 1994.
74. Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ, O'Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 332: 286-291, 1995.
75. Shaw GM, O'Malley CD, Wasserman CR, Tolarova MM, Lammer EJ. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet 59: 536-545, 1995.
76. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 268: 877-881, 1992.
77. Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, Colombo A, Schampaert E, Grube E, Kirtane AJ, Cutlip DE, Fahy M, Pocock SJ, Mehran R, Leon MB. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 356: 998-1008, 2007.
78. Stroes ES, van Faassen EE, Yo M, Martasek P, Boer P, Govers R, Rabelink TJ. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 86: 1129-1134, 2000.
79. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101: 948-954, 2000.
80. Tawakol A, Migrino RQ, Aziz KS, Waitkowska J, Holmvang G, Alpert NM, Muller JE, Fischman AJ, Gewirtz H. High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. J Am Coll Cardiol 45: 1580-1584, 2005.
81. Thomas GR, DiFabio JM, Gori T, Parker JD. Once daily therapy with isosorbide-5-mononitrate causes endothelial dysfunction in humans: evidence of a free-radical-mediated mechanism. J Am Coll Cardiol 49: 1289-1295, 2007.
82. Till U, Rohl P, Jentsch A, Till H, Muller A, Bellstedt K, Plonne D, Fink HS, Vollandt R, Sliwka U, Herrmann FH, Petermann H, Riezler R. Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, Vitamins B6 and B12. Atherosclerosis 181: 131-135, 2005.
83. Title LM, Cummings PM, Giddens K, Genest JJ Jr, Nassar BA. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 36: 758-765, 2000.
84. Torrens C, Brawley L, Anthony FW, Dance CS, Dunn R, Jackson AA, Poston L, Hanson MA. Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension 47: 982-987, 2006.
85. Touam M, Zingraff J, Jungers P, Chadefaux-Vekemans B, Drueke T, Massy ZA. Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy. Kidney Int 56: 2292-2296, 1999.
86. Tsutsumi T, Ichihara T, Kawabe M, Yoshino H, Asamoto M, Suzuki S, Shirai T. Renal toxicity induced by folic acid is associated with the enhancement of male reproductive toxicity of di(n-butyl)phthalate in rats. Reprod Toxicol 18: 35-42, 2004.
87. Ubbink JB, Becker PJ, Vermaak WJ, Delport R. Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem 41: 1033-1037, 1995.
88. Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Endothelial dysfunction by acute hyperhomocyst(e)inaemia: restoration by folic acid. Clin Sci (Lond) 96: 235-239, 1999.
89. Van Etten RW, de Koning EJ, Verhaar MC, Gaillard CA, Rabelink TJ. Impaired NO-dependent vasodilation in patients with Type II (non-insulin- dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia 45: 1004-1010, 2002.
90. Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, Pritchard KA Jr. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 95: 9220-9225, 1998.
91. Venn BJ, Green TJ, Moser R, Mann JI. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr 77: 658-662, 2003.
92. Verhaar MC, Wever RM, Kastelein JJ, van Dam T, Koomans HA, Rabelink TJ. 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation 97: 237-241, 1998.
93. Verhaar MC, Wever RM, Kastelein JJ, van Loon D, Milstien S, Koomans HA, Rabelink TJ. Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation 100: 335-338, 1999.
94. Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 81: 491-497, 1990.
95. Voutilainen S, Lakka TA, Porkkala-Sarataho E, Rissanen T, Kaplan GA, Salonen JT. Low serum folate concentrations are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Eur J Clin Nutr 54: 424-428, 2000.
96. Williams C, Kingwell BA, Burke K, McPherson J, Dart AM. Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype. Am J Clin Nutr 82: 26-31, 2005.
97. Wills L. Treatment of pernicious anaemia of pregnancy and tropical anaemia with special reference to yeast extracts as curative agent. Br Med J 1: 1059-1064, 1931.
98. Wilmink HW, Stroes ES, Erkelens WD, Gerritsen WB, Wever R, Banga JD, Rabelink TJ. Influence of folic acid on postprandial endothelial dysfunction. Arterioscler Thromb Vasc Biol 20: 185-188, 2000.
99. Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol 34: 2002-2006, 1999.
100. Yarnell JW, Sweetnam PM, Rumley A, Lowe GD. Lifestyle and hemostatic risk factors for ischemic heart disease : the Caerphilly Study. Arterioscler Thromb Vasc Biol 20: 271-279, 2000.
101. Zakrzewski SF, Nichol CA. Evidence for a single enzyme reducing folate and dihydrofolate. J Biol Chem 235: 2984-2988, 1960.