Murine models of hyperhomocysteinemia and their vascular phenotypes

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 28, Issue 9, 2008, Pages 1596-1605

  Dayal, Sanjana ^a   Lentz, Steven R ^a  

^a UNIVERSITY OF IOWA   (United States)

Author keywords

endothelium; homocysteine; hyperhomocysteinemia; murine models; thrombosis

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); CHOLINE; CYANOCOBALAMIN; CYSTATHIONINE BETA SYNTHASE; HOMOCYSTEINE; METHIONINE; PYRIDOXINE; BETAINE HOMOCYSTEINE METHYLTRANSFERASE; BHMT PROTEIN, MOUSE; ENZYME INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; CONTROLLED STUDY; DIETARY INTAKE; ENDOTHELIAL DYSFUNCTION; FOLIC ACID BLOOD LEVEL; GENETIC DISORDER; GENETIC MODEL; HUMAN; HYPERHOMOCYSTEINEMIA; INCIDENCE; METABOLISM; NONHUMAN; NUTRITIONAL ASSESSMENT; NUTRITIONAL DEFICIENCY; PATHOPHYSIOLOGY; PHENOTYPE; POPULATION; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SEX; THROMBOEMBOLISM; VASCULAR DISEASE; ANIMAL; DIET; DISEASE MODEL; DRUG ANTAGONISM; GENETIC PREDISPOSITION; MOUSE; THROMBOSIS; VASCULAR ENDOTHELIUM;

ANIMALS; BETAINE-HOMOCYSTEINE S-METHYLTRANSFERASE; DIET; DISEASE MODELS, ANIMAL; ENDOTHELIUM, VASCULAR; ENZYME INHIBITORS; GENETIC PREDISPOSITION TO DISEASE; HOMOCYSTEINE; HYPERHOMOCYSTEINEMIA; MICE; PHENOTYPE; THROMBOSIS;

EID: 51649112963     PISSN: 10795642     EISSN: None     Source Type: Journal    
DOI: 10.1161/ATVBAHA.108.166421     Document Type: Review

References (89)

1. Mudd SH, Finkelstein JD, Refsum H, Ueland PM, Malinow MR, Lentz SR, Jacobsen DW, Brattstrom L, Wilcken B, Wilcken DE, Blom HJ, Stabler SP, Allen RH, Selhub J. Rosenberg IH. Homocysteine and its disulfide derivatives: a suggested consensus terminology. Arterioscler Thromb Vasc Biol. 2000;20:1704-1706.
2. Selhub J, Jacques PF, Wilson PW, Rush. D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270:2693-2698.
3. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Scheuten EG. MTHFR 677C->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288:2023-2031.
4. Kruger WD, Wang L, Jhee KH, Singh RH, Elsas LJ II. Cystathionine β-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype. Hum Mutai. 2003;22:434-441.
5. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GH, Bromberg IL, Cerone R, et al. The natural, history of homocystinuria due to cystathionine β-synthase deficiency. Am J Hum Genet. 1985;37:1-31.
6. Watkins D, Ru M, Hwang HY, Kim CD, Murray A, Philip NS, Kim W, Legakis H, Wai T, Hilton JF, Ge B, Dore C, Hosack A, Wilson A, Gravel. RA, Shane B, Hudson TJ, Rosenblatt DS. Hyperhomocysteinemia due to methionine synthase deficiency, cbIG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. Am J Hum Genet. 2002;71:143 153.
7. Dierkes J, Westphal S. Effect of drugs on homocysteine concentrations. Semin Vasc Med. 2005;5:124-139.
8. van Guldener C, Stehouwer CD. Homocysteine and methionine metabolism in renal failure. Semin Vasc Med. 2005;5:201-208.
9. Tonetti C, Saudubray JM, Echenne B, Landrieu P, Giraudier S, Zittoun J. Relations between molecular and biological abnormalities in 11 families from siblings affected with metliylenetelrahydrofolate reductase deficiency. Eur J Pediatr. 2003;162:466-475.
10. Limal N, Scheuermaier K, Tazi Z, Sene D, Piette JC, Cacoub P. Hyperhomocysteinaemia, thrombosis and pernicious anaemia. Thromb Haemost. 2006;96:233-235.
11. Lentz SR, Haynes WG. Homocysteine: is it a clinically important cardiovascular risk factor? Cleve Clin J Med. 2004;71:729-734.
12. Homocysteine studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015-2022.
13. Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHER and risk of venous thrombosis: a meta-analysis of published, epidemiological studies. J Thromb Haemost. 2005;3:292 299.
14. Yap S, Boers GH, Wilcken B, Wilcken DE, Brenton DP, Lee PJ, Walter JH, Howard PM, Naughten ER. Vascular outcome in patients with homocystinuria due to cystathionine β-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol. 2001; 21:2080-2085.
15. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Amesen E, Rasmussen K. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006:354:1578-1588.
16. den Heijer M, Willems HP, Blom HJ, Gerrits WB, Cattaneo M, Eichinger S, Rosendaal FR, Bos GM. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: A randomized, placebo-controlled, double-blind trial. Blood. 2007;109: 139-144.
17. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr. Homocysteine lowering with folic acid and B vitamins in vascular disease. JV Engl J Med. 2006;354:1567 1577.
18. Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, Gaziano JM. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA, 2007;298:1163-1170.
19. Toole JF, Maiinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M. 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. 2004;291:565-575.
20. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007;369:1876-1882.
21. Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H, Friedman JM. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006;113:1335-1343.
22. Harker LA, Ross R, Slichter SJ, Scott CR. Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976;58:731-741.
23. Harker LA, Slichter SJ, Scott CR, Ross R. Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med. 1974;291:537-543.
24. Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Faraci FM, Mlalinow MR, Heistad DD. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest. 1996;98:24-29.
25. Rolland PH, Friggi A, Barlatier A, Piquet P, Latrille V, Faye MM, Guillou J, Charpiot P, Bodard H, Ghiringhelli O, et al. Hyperhomocysteinemia-induced vascular damage in the minipig. Captoprilhydrochlorothiazide combination prevents elastic alterations. Circulation. 1995:91:1161-1174.
26. Lang D, Kredan MB, Moat SJ, Hussain SA, Powell CA, Bellamy MF, Powers HJ, Lewis MJ. Homocysteine-induced inhibition of endothelium-dependent relaxation in rabbit aorta: role for superoxide anions. Arterioscler Thromb Vasc Biol. 2000:20:422 427.
27. Sauls DL, Lockhart E, Warren ME, Lenkowski A, Wilhelm SE, Hoffman M. Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism, of the thrombotic tendency in hyperhomocysteinemia. Biochemistry (Mosc). 2006;45: 2480-2487.
28. Bagi Z, Ungvari Z, Koller A. Xanthine oxidase-derived reactive oxygen species convert flow-induced arteriolar dilation to constriction in hyperhomocysteinemia: possible role of peroxynitrite. Arterioscler Thromb Vase Biol. 2002;22:28-33.
29. Morita H, Kurihara H, Yoshida S, Saito Y, Shindo T, Oh-Hashi Y, Kurihara Y, Yazaki Y, Nagai R. Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury. Circulation. 2001;103:133-139.
30. Symons JD, Rutledge JC, Simonsen U, Pattathu RA. Vascular dysfunction produced by hyperhomocysteinemia is more severe in the presence of low folate. Am J Physiol Heart Circ Physiol. 2006;290: H181-H191.
31. Elmore CL, Matthews RG. The many flavors of hyperhomocyst(e) inemia: insights from transgenic and inhibitor-based mouse models of disrupted one-carbon metabolism. Antioxid Redox Signal. 2007;9: 1911-1921.
32. Lentz SR. Mechanisms of homocysteine-induced atherothrombosis. J Thromb Haemost. 2005;3:1646-1654.
33. Westrick RJ, Winn ME, Eitzman DT. Murine models of vascular thrombosis. Arterioscler Thromb Vasc Biol. 2007;27:2079-2093.
34. Nutrient requirement of the mouse. In: Subcommittee on Animal Nutrition, Board on Agriculture, National Research Council. Nutrient requirements of laboratory animals. Fourth rev ed. Washington, DC: National Academy Press. 1995:80-102.
35. Schwann BC, Wendel U, Lussier-Cacan S, Mar MH, Zeisel SH, Leclerc D, Castro C, Garrow TA, Rozen R. Effects of betaine in a murine model of mild cystathionine β-synthase deficiency. Metabolism. 2004;53: 594-599.
36. Troen AM, Lutgens E, Smith DE, Rosenberg IH, Selhub J. The atherogenic effect of excess methionine intake. Proc Natl Acad Sei U S A. 2003;100:15089-15094.
37. Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf BM!, Tanji N, Ferran LJ Jr, Kohl B, Rao V, Kisiel W, Stem DM, Schmidt AM. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001;107:675-683.
38. Tan H, Jiang X, Yang F, Li Z, Liao D, Trial J, Magera MJ, Durante W, Yang X, Wang H. Hyperhomocysteinemia inhibits post-injury reendothelialization in mice. Cardiovasc Res. 2006;69:253 262.
39. Baumbach GL, Sigmund CD, Bottiglieri T, Lentz SR. Structure of cerebral arterioles in cystathionine β-synthase-deficient mice. Circ Res. 2002;91:931-937.
40. Dayal S, Arning E, Bottiglieri T, Boger RH, Sigmund CD, Faraci FM, Lentz SR. Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke. 2004;35:1957-1962.
41. Dayal S, Bottiglieri T, Arning E, Maeda N, Malinow MR, Sigmund CD, Heistad DD, Faraci FM, Lentz SR. Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine β-synthase-deficient mice. Circ Res. 2001;88:1203-1209.
42. Dayal S, Brown KL, Weydert CJ, Oberley LW, Arning E, Bottiglieri T, Faraci FM, Lentz SR. Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to endothelial dysfunction. Arterioscler Thromb Vasc Biol. 2002;22:1996 2002.
43. Devlin AM, Arning E, Bottiglieri T, Faraci FM, Rozen R, Lentz SR. Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice. Blood. 2004;103:2624-2629.
44. Werstuck GH, Lentz, SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Mlaeda N, Krisans SK, Mlalinow MR, Austin RC. Homocysteineinduced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest. 2001;107: 1263-1273.
45. Wang L, Jhee KH, Hua X, DiBello PM, Jacobsen DW, Kruger WD. Modulation of cystathionine β-synthase level regulates total, serum, homocysteine in mice. Circ Res. 2004;94:1318-1324.
46. Zhou J, Moller J, Danielsen CC, Bentzon J, Ravn HB, Austin RC, Falk E. Dietary supplementation with, methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vase Biol. 2001;21:1470-1476.
47. Cottington EM, LaMantia C, Stabler SP, Alien RH, Tangerman A, Wagner C, Zeisel SH, Mudd. SH. Adverse event associated with methionine loading test: a case report. Arterioscler Thromb Vasc Biol. 2002;22:1046-1050.
48. Lentz, SR, Erger RA, Dayal S, Maeda N, Malinow MR, Heistad DD, Faraci FM. Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine β-synthase-deficient mice. Am J Physiol Heart Circ Physiol, 2000;279:H970-H975.
49. Symons JD, Zaid UB, Athanassious CN, Mullick AE, Lentz SR, Rutledge JC. Influence of folate on arterial permeability and stiffness in the absence or presence of hyperhomocysteinemia. Arterioscler Thromb Vasc Biol. 2006:26:814-818.
50. Gospe SM Jr, Gietzen DW, Summers PJ, Lunetta JM, Miller JW, Selhub J., Ellis WG, Clifford AJ. Behavioral and neurochemical changes in folate-deficient mice. Physiol Behav. 1995;58:935-941.
51. Li D, Pickell L, Liu Y, Rozen R. Impact of methylenetetrahydrofolate reductase deficiency and low dietary folate on the development of neural tube defects in splotch mice. Birth Defects Res A Clin Mol Teratol. 2006:76:55 59.
52. Li D, Rozen R. Matemal folate deficiency affects proliferation, but not apoptosis, in embryonic mouse heart. J Nutr. 2006;136:1774-1778.
53. da Costa KA, Gaffney CE, Fischer LM, Zeisel SH. Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load. Am J Clin Nutr. 2005;81:440-444.
54. Robert K, Nehme J, Bourdon E, Pivert G, Friguet B, Delcayre C, Delabar JM, Janel N. Cystathionine β-synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liver. Gastroenterology. 2005;128: 1405-1415.
55. Schwahn BC, Laryea MD, Chen Z, Melnyk S, Pogribny I, Garrow T, .lames SJ, Rozen R. Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency. Biochem J. 2004:382:831-840.
56. Thampi P, Stewart BW, Joseph L, Melnyk SB, Hennings LJ, Nagarajan S. Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression. Atherosclerosis. 2008:1.97: 620-629.
57. Zhou J, Moller J, Ritskes-Hoitinga M, Larsen ML, Austin RC, Falk E. Effects of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. Atherosclerosis. 2003;168:255-262.
58. Dayal S, Devlin AM, McCaw RB, Liu ML, Arning E, Bottiglieri T, Shane B, Faraci FM, Lentz SR. Cerebral vascular dysfunction in methionine synthase-deficient mice. Circulation. 2005:112:737-744.
59. Doshi SN, McDowell IF, Moat SJ, Payne N, Durrant HJ, Lewis MJ, Goodfellow J. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation. 2002:105:22 26.
60. Watenabe M, Osada J, Aratani Y, Kluckman K, Reddick R, Malinow MR, Maeda N. Mice deficient in cystathionine β-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci U S A. 1995;92:1585-1589.
61. Jiang X, Yang F, Tan H, Liao D, Bryan RM Jr, Randhawa JK, Rumbaut RE, Durante W, Schafer AI, Yang X, Wang H. Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC activation. Arterioscler Thromb Vasc Biol. 2005;25:2515-2521.
62. Eberhardt RT, Forgione MA, Cap A, Leopold JA, Rudd MA, Trolliet M, Heydrick S, Stark R, Klings ES, Moldovan NI, Yaghoubi M, Goldschmidt-Clermont PJ, Färber HW, Cohen R, Loscalzo J. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest. 2000;106:483-491.
63. Weiss N, Heydrick S, Zhang YY, Bierl C, Cap A, Loscalzo J. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine β-synthase-deficient mice. Arterioscler Thromb Vasc Biol. 2002;22:34-41.
64. Wang L, Chen X, Tang B, Hua X, Klein-Szanto A, Kruger WD. Expression of mutant human cystathionine β-synthase rescues neonatal lethality but not homocystinuria in a mouse model. Hum Mol Genet. 2005;14:2201-2208.
65. Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Mlelnyk S, Lussier-Cacan S, Chen MF, Pai A, John SW, Smith RS, Bottiglieri T, Bagley P, Selhub J, Rudnicki MA, James SJ, Rozen R. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhoiiiocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet. 2001;10:433-443.
66. Virdis A, Iglarz M, Neves MF, Amiri F, Touyz RM, Rozen R, Schiffrin EL. Effect of hyperhomocystinemia and hypertension on endothelial function in methylenetetrahydrofolate reductase-deficient mice. Arterioscler Thromb Vase Biol. 2003:23:1352-1357.
67. Swanson DA, Liu ML, Baker PJ, Garrett L, Stitzel M, Wu J, Harris M, Banerjee R, Shane B, Brody LC. Targeted disruption of the methionine synthase gene in mice. Mol Cell Biol. 2001;21:1058-1065.
68. Elmore CL, Wu X, Leclerc D, Watson ED, Bottiglieri T, Krupenko NI, Krupenko SA, Cross JC, Rozen R, Gravel RA, Matthews RG. Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase. Mol Genet Metab. 2007;91:85-97.
69. Dayal S, Wilson KM, Leo L, Arning E, Bottiglieri T, Lentz SR. Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia. Blood, 2006;108:2237-2243.
70. Lentz SR, Piegors DJ, Fernandez JA, Erger RA, Arning E, Malinow MR, Griffin JH, Bottiglieri T, Haynes WG, Heistad DD. Effect of hyperhomocysteinemia on protein C activation and activity. Blood, 2002;100: 2108-2112.
71. Hanson NQ, Aras O, Yang F, Tsai MY. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem. 2001;47:661-666.
72. Tsai MY, Garg U, Key NS, Hanson NQ, Suh A, Schwichtenberg K. Molecular and biochemical approaches in the identification of heterozygotes for homocystinuria. Atherosclerosis. 1996;122:69-77.
73. Collinsova M, Strakova J, Jiracek J, Garrow TA. Inhibition of betainehomocysteine S-methyltransferase causes hyperhomocysteinemia in mice. J Nutr. 2006;136:1493-1497.
74. Andersson A, Brattstrom L, Israelsson B, Isaksson A, Hamfelt A, Hultberg B. Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest. 1992;22:79-87.
75. Lussier-Cacan S, Xhignesse M, Piolot A, Selhub J, Davignon J, Genest J Jr. Plasma total homocysteine in healthy subjects: sex-specific relation with biological traits. Am J Clin Nutr. 1996;64:587-593.
76. Vitvitsky V, Prudova A, Stabler S, Dayal S, Lentz SR, Banerjee R. Testosterone regulation of renal, cystathionine β-synthase: implications for sex-dependent differences in plasma homocysteine levels. Am J Physiol Renal Physiol. 2007;293:F594-F600.
77. Wilson KM, McCaw RB, Leo L, Arning E, Lhotek S, Bottiglieri T, Austin RC, Lentz SR. Prothrombotic effects of hyperhomocysteinemia and hypercholesterolemia in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2007;27:233-240.
78. Stevens JC, Banks GT, Festing MF, Fisher EM. Quiet mutations in inbred strains of mice. Trends Mol Med. 2007;13:512-519.
79. Devlin AM, Bottiglieri T, Domann FE, Lentz SR. Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia. J Biol Chem. 2005:280:25506-25511.
80. Velez-Carrasco W, Merkel M, Twiss CO, Smith JD. Dietary methionine effects on plasma homocysteine and HDL metabolism in mice. J Nutr Biochem. 2008;19:362-370.
81. Dayal S, Lentz SR. Role of redox reactions in the vascular phenotype of hyperhomocysteinemic animals. Antioxid Redox Signal. 2007;9: 1899 1909.
82. Mullick AE, Zaid. UB, Athanassious CN, Lentz SR, Rutledge JC, Symons JD. Hyperhomocysteinemia increases arterial permeability and stiffness in mice. Am J Physiol Regul Integr Comp Physiol. 2006;291: R1349 R1354.
83. Ovechkin AV, Tyagi N, Sen U, Lominadze D, Steed MM, Moshai KS, Tyagi SC. 3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice. Am J Physiol Lung Cell Mol Physiol. 2006;291:L905 L911.
84. Zhou J, Werstuck GH, Lhotak S, Shi YY, Tedesco V, Trigatti B, Dickhout J, Majors AK, Dibello PM, Jacobsen DW, Austin RC. Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL/6J mice. FASEB J. In press.
85. Dai J, Li W, Chang L, Zhang Z, Tang C, Wang N, Zhu Y, Wang X. Role of redox factor-1 in hyperhomocysteinemia-accelerated atherosclerosis. Free Radic Biol Med. 2006:41:1566-1577.
86. Wang H, Jiang X, Yang F, Gaubatz JW, Ma L, Magera MJ, Yang X, Berger PB, Durante W, Pownall HJ, Schafer AI. Hyperhomocysteinemia accelerates atherosclerosis in cystathionine β-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation. Blood. 2003:101:3901 3907.
87. Loscalzo J. Homocysteine trials-clear outcomes for complex reasons. N Engl J Med. 2006;354:1629-1632.
88. Vitvitsky V, Dayal S, Stabler S, Zhou Y, Wang H, Lentz SR, Banerjee R. Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia. Am J Physiol Regul Integr Comp Physiol. 2004;287:R39-R46.
89. Kamath AF, Chauhan AK, Kisucka J, Dole VS, Loscalzo J, Handy DE, Wagner DD. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood. 2006;107:591-593.