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Molecular targeting by homocysteine: a mechanism for vascular pathogenesis

  • Donald W. Jacobsen , Otilia Catanescu , Patricia M. DiBello and John C. Barbato
Published/Copyright: September 21, 2011
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 43 Issue 10

Abstract

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Although there is a growing body of evidence that homocysteine plays a causal role in atherogenesis, specific mechanisms to explain the underlying pathology have remained elusive. This review focuses on chemistry unique to the homocysteine molecule to explain its inherent cytotoxicity. Thus, the high pKa of the sulfhydryl group (pKa=10.0) of homocysteine underlies its ability to form stable disulfide bonds with protein cysteine residues, and in the process, alters or impairs the function of the protein. Albumin, fibronectin, transthyretin, annexin II, and factor V have now been identified as molecular targets for homocysteine, and in the case of albumin, the mechanism of targeting has been elucidated.

Keywords: albumin; atherogenesis; disulfide bond; glutathione peroxidase; homocysteine; hyperhomocysteinemia; molecular targeting; pKa; sulfhydryl group; vascular pathogenesis
Corresponding author: Donald W. Jacobsen, PhD, Department of Cell Biology, NC-10, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA Phone: +1-216-444-8340, Fax: +1-216-445-5480,

References

1. Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem 1990; 1:228–37.10.1016/0955-2863(90)90070-2Search in Google Scholar

2. Chen P, Poddar R, Tipa EV, DiBello PM, Moravec CD, Robinson K, et al. Homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease. Adv Enzyme Regul 1999; 39:93–109.10.1016/S0065-2571(98)00029-6Search in Google Scholar

3. Nygård O, Vollset SE, Refsum H, Brattström L, Ueland PM. Total homocysteine and cardiovascular disease. J Intern Med 1999; 246:425–54.10.1046/j.1365-2796.1999.00512.xSearch in Google Scholar

4. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998; 55:1449–55.10.1001/archneur.55.11.1449Search in Google Scholar

5. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002; 346:476–83.10.1056/NEJMoa011613Search in Google Scholar

6. Vollset SE, Refsum H, Irgens LM, Emblem BM, Tverdal A, Gjessing HK, et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J Clin Nutr 2000; 71:962–8.10.1093/ajcn/71.4.962Search in Google Scholar

7. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, van der Klift M, de Jonge R, Lindemans J, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 2004; 350:2033–41.10.1056/NEJMoa032546Search in Google Scholar

8. McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004; 350:2042–9.10.1056/NEJMoa032739Search in Google Scholar

9. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337:230–6.10.1056/NEJM199707243370403Search in Google Scholar

10. Taylor LM Jr, Moneta GL, Sexton GJ, Schuff RA, Porter JM. Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. J Vasc Surg 1999; 29:8–19.10.1016/S0741-5214(99)70345-9Search in Google Scholar

11. Bostom AG, Culleton BF. Hyperhomocysteinemia in chronic renal disease. J Am Soc Nephrol 1999; 10:891–900.10.1681/ASN.V104891Search in Google Scholar PubMed

12. Eichinger S, Stümpflen A, Hirschl M, Bialonczyk C, Herkner K, Stain M, et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80:566–9.Search in Google Scholar

13. Stehouwer CDA, Gall MA, Hougaard P, Jakobs C, Parving HH. Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria. Kidney Int 1999; 55:308–14.10.1046/j.1523-1755.1999.00256.xSearch in Google Scholar PubMed

14. Mudd SH, Levy HL, Kraus JP. Disorders of trans-sulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease, 8th ed. New York: McGraw-Hill, 2001:2007–56.Search in Google Scholar

15. Weiss N, Keller C, Hoffmann U, Loscalzo J. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia. Vasc Med 2002; 7:227–39.10.1191/1358863x02vm428raSearch in Google Scholar PubMed

16. Weiss N, Heydrick SJ, Postea O, Keller C, Keaney JF Jr, Loscalzo J. Influence of hyperhomocysteinemia on the cellular redox state – impact on homocysteine-induced endothelial dysfunction. Clin Chem Lab Med 2003; 41:1455–61.10.1515/CCLM.2003.223Search in Google Scholar PubMed

17. Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 2004; 11(Suppl 1):S56–64.10.1038/sj.cdd.4401451Search in Google Scholar PubMed

18. Moat SJ, Lang D, McDowell IF, Clarke ZL, Madhavan AK, Lewis MJ, et al. Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem 2004; 15:64–79.10.1016/j.jnutbio.2003.08.010Search in Google Scholar PubMed

19. Weiss N. Mechanisms of increased vascular oxidant stress in hyperhomocysteinemia and its impact on endothelial function. Curr Drug Metab 2005; 6:27–36.10.2174/1389200052997357Search in Google Scholar PubMed

20. Poddar R, Sivasubramanian N, DiBello PM, Robinson K, Jacobsen DW. Homocysteine induces expression and secretion of MCP-1 and IL-8 in human aortic endothelial cells: implications for vascular disease. Circulation 2001; 103:2717–23.10.1161/01.CIR.103.22.2717Search in Google Scholar

21. Tsai J-C, Perrella MA, Yoshizumi M, Hsieh CM, Haber E, Schlegel R, et al. Promotion of vascular smooth muscle growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci USA 1994; 91:6369–73.10.1073/pnas.91.14.6369Search in Google Scholar PubMed PubMed Central

22. Lentz SR. Homocysteine and cardiovascular physiology. In: Carmel R, Jacobsen DW, editors. Homocysteine in health and disease. Cambridge, UK: Cambridge University Press, 2001:441–50.Search in Google Scholar

23. Zou C-G, Banerjee R. Homocysteine and redox signaling. Antioxid Redox Signal 2005; 7;547–59.10.1089/ars.2005.7.547Search in Google Scholar PubMed

24. Kang S-S, Wong PWK, Becker N. Protein-bound homocyst(e)ine in normal subjects and in patients with homocystinuria. Pediatr Res 1979; 13:1141–3.10.1203/00006450-197910000-00012Search in Google Scholar

25. Malloy MH, Rassin DK, Gaull GE. Plasma cysteine in homocysteinemia. Am J Clin Nutr 1981; 34:2619–21.10.1093/ajcn/34.12.2619Search in Google Scholar

26. Smolin LA, Benevenga NJ. Accumulation of homocyst(e)ine in vitamin B6 deficiency: a model for the study of cystathionine B-synthase deficiency. J Nutr 1982; 112:1264–72.10.1093/jn/112.7.1264Search in Google Scholar

27. Refsum H, Helland S, Ueland PM. Radioenzymic determination of homocysteine in plasma and urine. Clin Chem 1985; 31:624–8.10.1093/clinchem/31.4.624Search in Google Scholar

28. Kang S-S, Wong PWK, Cook HY, Norusis M, Messer JV. Protein-bound homocysteine: a possible risk factor for coronary artery disease. J Clin Invest 1986; 77:1482–6.10.1172/JCI112461Search in Google Scholar

29. Sartorio R, Carrozzo R, Corbo L, Andria G. Protein-bound plasma homocyst(e)ine and identification of heterozygotes for cystathionine-synthase deficiency. J Inherit Metab Dis 1986; 9:25–9.10.1007/BF01813897Search in Google Scholar

30. Wiley VC, Dudman NP, Wilcken DE. Interrelations between plasma free and protein-bound homocysteine and cysteine in homocystinuria. Metabolism 1988; 37:191–5.10.1016/S0026-0495(98)90017-8Search in Google Scholar

31. Wiley VC, Dudman NP, Wilcken DE. Free and protein-bound homocysteine and cysteine in cystathionine β-synthase deficiency: interrelations during short- and long-term changes in plasma concentrations. Metabolism 1989; 38:734–9.10.1016/0026-0495(89)90058-9Search in Google Scholar

32. Smolin LA, Benevenga NJ. The use of cyst(e)ine in the removal of protein-bound homocysteine. Am J Clin Nutr 1984; 39:730–7.10.1093/ajcn/39.5.730Search in Google Scholar PubMed

33. Wilcken DE, Wilcken B. The pathogenesis of coronary artery disease: a possible role for methionine metabolism. J Clin Invest 1976; 57:1079–82.10.1172/JCI108350Search in Google Scholar PubMed PubMed Central

34. Mansoor MA, Svardal AM, Ueland PM. Determination of the in vivo redox status of cysteine, cysteinylglycine, homocysteine, and glutathione in human plasma. Anal Biochem 1992; 200:218–29.10.1016/0003-2697(92)90456-HSearch in Google Scholar

35. Mansoor MA, Ueland PM, Aarsland A, Svardal AM. Redox status and protein binding of plasma homocysteine and other aminothiols in patients with homocystinuria. Metabolism 1993; 42:1481–5.10.1016/0026-0495(93)90202-YSearch in Google Scholar

36. Mansoor MA, Ueland PM, Svardal AM. Redox status and protein binding of plasma homocysteine and other aminothiols in patients with hyperhomocysteinemia due to cobalamin deficiency. Am J Clin Nutr 1994; 59:631–5.10.1093/ajcn/59.3.631Search in Google Scholar PubMed

37. Mansoor MA, Bergmark C, Svardal AM, Lonning PE, Ueland PM. Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Homocysteine and peripheral vascular disease. Arterioscler Thromb Vasc Biol 1995; 15:232–40.10.1161/01.ATV.15.2.232Search in Google Scholar

38. Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004; 50:3–32.10.1373/clinchem.2003.021634Search in Google Scholar PubMed

39. Jakubowski H. Molecular basis of homocysteine toxicity in humans. Cell Mol Life Sci 2004; 61:470–87.10.1007/s00018-003-3204-7Search in Google Scholar PubMed

40. He XM, Carter DC. Atomic structure and chemistry of human serum albumin. Nature 1992; 358:209–15.10.1038/358209a0Search in Google Scholar PubMed

41. Peters T Jr. All about albumin: biochemistry, genetics, and medical applications. San Diego, CA: Academic Press, 1996:51–4.Search in Google Scholar

42. Sengupta S, Chen H, Togawa T, DiBello PM, Majors AK, Büdy B, et al. Albumin thiolate anion is an intermediate in the formation of albumin-S-S-homocysteine. J Biol Chem 2001; 276:30111–7.10.1074/jbc.M104324200Search in Google Scholar PubMed

43. Büdy B, Sengupta S, DiBello PM, Kinter M, Jacobsen DW. A facile synthesis of homocysteine-cysteine mixed disulfide. Anal Biochem 2001; 291:303–5.10.1006/abio.2000.5039Search in Google Scholar PubMed

44. Sengupta S, Wehbe C, Majors AK, Ketterer ME, DiBello PM, Jacobsen DW. Relative roles of albumin and ceruloplasmin in the formation of homocysteine, homocysteine-cysteine mixed disulfide, and cystine in circulation. J Biol Chem 2001; 276:46896–904.10.1074/jbc.M108451200Search in Google Scholar PubMed

45. Benson MD. Amyloidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease, 8th ed. New York: McGraw-Hill, 2001:5345–78.Search in Google Scholar

46. Théberge R, Conners L, Skinner M, Costello CE. Characterization of transthyretin from serum using immunoprecipitation, HPLC/electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry. Anal Chem 1999; 71:452–9.10.1021/ac980531uSearch in Google Scholar

47. Kishikawa M, Nakanishi T, Miyazaki A, Shimizu A. A simple and reliable method of detecting variant transthyretins by multidimensional liquid chromatography coupled to electrospray ionization mass spectrometry. Amyloid 1999; 6:48–53.10.3109/13506129908993287Search in Google Scholar

48. Lim A, Sengupta S, McComb ME, Théberge R, Wilson WG, Costello CE, et al. In vitro and In vivo interactions of homocysteine with human plasma transthyretin. J Biol Chem 2003; 278:49707–13.10.1074/jbc.M306748200Search in Google Scholar

49. Cornwell GG, Murdoch WL, Kyle RA, Westermark P, Pitkänen P. Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation. Am J Med 1983; 75:618–23.10.1016/0002-9343(83)90443-6Search in Google Scholar

50. Undas A, Williams EB, Butenas S, Orfeo T, Mann KG. Homocysteine inhibits inactivation of Factor Va by activated protein C. J Biol Chem 2001; 276:4389–97.10.1074/jbc.M004124200Search in Google Scholar PubMed

51. Lentz SR, Piegors DJ, Fernández JA, Erger RA, Arning E, Malinow MR. Effects of hyperhomocysteinemia on protein C activation and activity. Blood 2002; 100:2108–12.10.1182/blood-2002-03-0727Search in Google Scholar PubMed

52. Wild SH, Fortmann SP, Marcovina SM. A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants. Arterioscler Thromb Vasc Biol 1997; 17:239–45.10.1161/01.ATV.17.2.239Search in Google Scholar

53. Herrmann W, Quast S, Ellgass A, Wolter K, Kiessig ST, Molinari E, et al. An increased serum level of free apo(a) in renal patients is more striking than that of Lp(a) and is influenced by homocysteine. Nephron 2000; 85:41–9.10.1159/000045628Search in Google Scholar PubMed

54. Foody JM, Milberg JA, Robinson K, Pearce GL, Jacobsen DW, Sprecher DL. Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women. Arterioscler Thromb Vasc Biol 2000; 20:493–9.10.1161/01.ATV.20.2.493Search in Google Scholar PubMed

55. Harpel PC, Chang VT, Borth W. Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. Proc Natl Acad Sci USA 1992; 89:10193–7.10.1073/pnas.89.21.10193Search in Google Scholar PubMed PubMed Central

56. Majors AK, Sengupta S, Willard B, Kinter MT, Pyeritz RE, Jacobsen DW. Homocysteine binds to human plasma fibronectin and inhibits its interaction with fibrin. Arterioscler Thromb Vasc Biol 2002; 22:1354–9.10.1161/01.ATV.0000023899.93940.7CSearch in Google Scholar

57. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease – enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol 1997; 17:2074–81.10.1161/01.ATV.17.10.2074Search in Google Scholar

58. Majors AK, Sengupta S, Jacobsen DW, Pyeritz RE. Upregulation of smooth muscle cell collagen production by homocysteine-insight into the pathogenesis of homocystinuria. Mol Genet Metab 2002; 76:92–9.10.1016/S1096-7192(02)00030-6Search in Google Scholar

59. Zhou J, Moller J, Danielsen CC, Bentzon J, Ram HB, Austin RC, et al. Dietary supplement with methionine and homocysteine promotes early atherogenesis but not plaque rupture in apoE-deficient mice. Arterioscler Thromb Vasc Biol 2001; 21:1470–6.10.1161/hq0901.096582Search in Google Scholar

60. Lubec B, Labudova O, Hoeger H, Muehl A, Fang-Kircher S, Mark M, et al. Homocysteine increases cyclin-dependent kinase in aortic rat tissue. Circulation 1996; 94:2620–5.10.1161/01.CIR.94.10.2620Search in Google Scholar

61. Burke AP, Fonseca V, Kolodgie F, Zieske A, Fink L, Virmani R. Increased serum homocysteine and sudden death resulting from coronary atherosclerosis with fibrous plaques. Arterioscler Thromb Vasc Biol 2002; 22:1936–41.10.1161/01.ATV.0000035405.16217.86Search in Google Scholar

62. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56:111–28.Search in Google Scholar

63. Bescond A, Augier T, Chareyre C, Garçon D, Hornebeck W, Charpiot P. Influence of homocysteine on matrix metalloproteinase 2. Activation and activity. Biochem Biophys Res Commun 1999; 263:498–503.10.1006/bbrc.1999.1391Search in Google Scholar

64. Murphy G, Docherty JP. The matrix metalloproteinases and their inhibitors. Am J Respir Cell Mol Biol 1992; 7:120–5.10.1165/ajrcmb/7.2.120Search in Google Scholar

65. Hajjar KA, Jacovina AT. Modulation of annexin II by homocysteine: implications for atherothrombosis. J Investig Med 1998; 46:364–9.Search in Google Scholar

66. Hajjar KA, Harpel PC, Jaffe EA, Nachman RL. Binding of plasminogen to cultured human endothelial cells. J Biol Chem 1986; 261:11656–62.10.1016/S0021-9258(18)67293-XSearch in Google Scholar

67. Hajjar KA, Mauri L, Jacovina AT, Zhong F, Mirza UA, Padovan JC, et al. Tissue plasminogen activator binding to the annexin II tail domain − direct modulation by homocysteine. J Biol Chem 1998; 273:9987–93.10.1074/jbc.273.16.9987Search in Google Scholar PubMed

68. Weiss N, Heydrick S, Zhang Y-Y, Bierl C, Cap A, Loscalzo J. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine β-synthase-deficient mice. Arterioscler Thromb Vas Biol 2002; 22;34–41.10.1161/hq1201.100456Search in Google Scholar PubMed

69. Huang R-FS, Hsu Y-C, Lin H-L, Yang FL. Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers. J Nutr 2001; 131:33–8.10.1093/jn/131.1.33Search in Google Scholar PubMed

70. Weiss N, Zhang Y-Y, Heydrick S, Bierl C, Loscalzo J. Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction. Proc Natl Acad Sci USA 2001; 98:12503–8.10.1073/pnas.231428998Search in Google Scholar PubMed PubMed Central

71. Nishio E, Watanabe Y. Homocysteine as a modulator of platelet-derived growth factor action in vascular smooth muscle cells: a possible role for hydrogen peroxide. Br J Pharmacol 1997; 122:269–74.10.1038/sj.bjp.0701391Search in Google Scholar PubMed PubMed Central

72. Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, et al. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997; 272:17012–7.10.1074/jbc.272.27.17012Search in Google Scholar PubMed

73. Handy DE, Zhang Y, Loscalzo J. Homocysteine down-regulates cellular glutathione peroxidase (GPx1) by decreasing translation. J Biol Chem 2005; 280:15518–25.10.1074/jbc.M501452200Search in Google Scholar PubMed

74. Böger RH, Bode-Böger SM, Sydow K, Heistad DD, Lentz SR. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000; 20:1557–64.10.1161/01.ATV.20.6.1557Search in Google Scholar

75. Stühlinger MK, Tsao PS, Her J-H, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway role of asymmetric dimethylarginine. Circulation 2001; 104:2569–75.10.1161/hc4601.098514Search in Google Scholar PubMed

76. Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 1991; 88:1906–14.10.1172/JCI115514Search in Google Scholar PubMed PubMed Central

77. Hayashi T, Honda G, Suzuki K. An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells. Blood 1992; 79:2930–6.10.1182/blood.V79.11.2930.2930Search in Google Scholar

78. Lentz SR, Sadler JE. Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. Blood 1993; 81:683–9.10.1182/blood.V81.3.683.683Search in Google Scholar

79. Kokame K, Kato H, Miyata T. Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis − GRP78/BiP and novel genes. J Biol Chem 1996; 271:29659–65.10.1074/jbc.271.47.29659Search in Google Scholar PubMed

80. Outinen PA, Sood SK, Liaw PCY, Sarge KD, Maedna N, Hirsch J, et al. Characterization of the stress-inducing effects of homocysteine. Biochem J 1998; 332:213–21.10.1042/bj3320213Search in Google Scholar PubMed PubMed Central

81. Outinen PA, Sood SK, Pfeifer SI, Pamidi S, Podor TJ, Li J, et al. Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood 1999; 94:959–67.10.1182/blood.V94.3.959.415k20_959_967Search in Google Scholar

82. Zhang C, Cai Y, Adachi MT, Oshiro S, Aso T, Kaufman RJ, et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. J Biol Chem 2001; 276:35867–74.10.1074/jbc.M100747200Search in Google Scholar PubMed

83. Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, et al. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 2001; 107:1263–73.10.1172/JCI11596Search in Google Scholar PubMed PubMed Central

84. Hossain GS, van Thienen JV, Werstuck G, Zhou J, Sood SK, Dickhout JG, et al. TDAGG51 is induced by homocysteine, promotes detachment-mediated programmed cell death and contributes to the development of atherosclerosis in hyperhomocysteinemia. J Biol Chem 2003; 278:30317–27.10.1074/jbc.M212897200Search in Google Scholar PubMed

Published Online: 2011-9-21
Published in Print: 2005-10-1

©2005 by Walter de Gruyter Berlin New York

Articles in the same Issue

  1. Homocysteine research – where do we stand and where are we going?
  2. Hyperhomocysteinemia and arteriosclerosis: historical perspectives
  3. Homocysteine and heart failure: a review of investigations from the Framingham Heart Study
  4. Homocysteine and vascular disease in diabetes: a double hit?
  5. Reduced adenosine receptor stimulation as a pathogenic factor in hyperhomocysteinemia
  6. Effects of homocysteine on vascular and tissue adenosine: a stake in homocysteine pathogenicity?
  7. Anti-N-homocysteinylated protein autoantibodies and cardiovascular disease
  8. Carotid narrowing degree and plasma thiol levels in carotid endarterectomy patients
  9. Impairment of homocysteine metabolism in patients with retinal vascular occlusion and non-arteritic ischemic optic neuropathy
  10. Hyperhomocysteinaemia in chronic kidney disease: focus on transmethylation
  11. Hyperhomocysteinemia and macromolecule modifications in uremic patients
  12. Hyperhomocysteinemia and response of methionine cycle intermediates to vitamin treatment in renal patients
  13. Vitamin B12 deficiency is the dominant nutritional cause of hyperhomocysteinemia in a folic acid-fortified population
  14. Homocysteine, folic acid and vitamin B12 in relation to pre- and postnatal health aspects
  15. Evaluation of the technical performance of novel holotranscobalamin (holoTC) assays in a multicenter European demonstration project
  16. A laboratory algorithm with homocysteine as the primary parameter reduces the cost of investigation of folate and cobalamin deficiency
  17. Betaine: a key modulator of one-carbon metabolism and homocysteine status
  18. Molecular targeting by homocysteine: a mechanism for vascular pathogenesis
  19. Anti-inflammatory compound resveratrol suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells in vitro
  20. Homocysteine in relation to cognitive performance in pathological and non-pathological conditions
  21. Homocysteine and B vitamins in mild cognitive impairment and dementia
  22. Homocysteine, type 2 diabetes mellitus, and cognitive performance: The Maine-Syracuse Study
  23. Plasma homocysteine levels in L-dopa-treated Parkinson's disease patients with cognitive dysfunctions
  24. Homocysteine – a newly recognised risk factor for osteoporosis
  25. Relation between homocysteine and biochemical bone turnover markers and bone mineral density in peri- and post-menopausal women
  26. Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality
  27. Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance
  28. Concentrations of homocysteine, related metabolites and asymmetric dimethylarginine in preeclamptic women with poor nutritional status
  29. Asymmetric dimethylarginine, homocysteine and renal function – is there a relation?
  30. Interactions between folate and aging for carcinogenesis
  31. The potential cocarcinogenic effect of vitamin B12 deficiency
  32. The vegetarian lifestyle and DNA methylation
https://doi.org/10.1515/CCLM.2005.188
Keywords for this article
albumin; atherogenesis; disulfide bond; glutathione peroxidase; homocysteine; hyperhomocysteinemia; molecular targeting; pKa; sulfhydryl group; vascular pathogenesis

Articles in the same Issue

  1. Homocysteine research – where do we stand and where are we going?
  2. Hyperhomocysteinemia and arteriosclerosis: historical perspectives
  3. Homocysteine and heart failure: a review of investigations from the Framingham Heart Study
  4. Homocysteine and vascular disease in diabetes: a double hit?
  5. Reduced adenosine receptor stimulation as a pathogenic factor in hyperhomocysteinemia
  6. Effects of homocysteine on vascular and tissue adenosine: a stake in homocysteine pathogenicity?
  7. Anti-N-homocysteinylated protein autoantibodies and cardiovascular disease
  8. Carotid narrowing degree and plasma thiol levels in carotid endarterectomy patients
  9. Impairment of homocysteine metabolism in patients with retinal vascular occlusion and non-arteritic ischemic optic neuropathy
  10. Hyperhomocysteinaemia in chronic kidney disease: focus on transmethylation
  11. Hyperhomocysteinemia and macromolecule modifications in uremic patients
  12. Hyperhomocysteinemia and response of methionine cycle intermediates to vitamin treatment in renal patients
  13. Vitamin B12 deficiency is the dominant nutritional cause of hyperhomocysteinemia in a folic acid-fortified population
  14. Homocysteine, folic acid and vitamin B12 in relation to pre- and postnatal health aspects
  15. Evaluation of the technical performance of novel holotranscobalamin (holoTC) assays in a multicenter European demonstration project
  16. A laboratory algorithm with homocysteine as the primary parameter reduces the cost of investigation of folate and cobalamin deficiency
  17. Betaine: a key modulator of one-carbon metabolism and homocysteine status
  18. Molecular targeting by homocysteine: a mechanism for vascular pathogenesis
  19. Anti-inflammatory compound resveratrol suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells in vitro
  20. Homocysteine in relation to cognitive performance in pathological and non-pathological conditions
  21. Homocysteine and B vitamins in mild cognitive impairment and dementia
  22. Homocysteine, type 2 diabetes mellitus, and cognitive performance: The Maine-Syracuse Study
  23. Plasma homocysteine levels in L-dopa-treated Parkinson's disease patients with cognitive dysfunctions
  24. Homocysteine – a newly recognised risk factor for osteoporosis
  25. Relation between homocysteine and biochemical bone turnover markers and bone mineral density in peri- and post-menopausal women
  26. Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality
  27. Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance
  28. Concentrations of homocysteine, related metabolites and asymmetric dimethylarginine in preeclamptic women with poor nutritional status
  29. Asymmetric dimethylarginine, homocysteine and renal function – is there a relation?
  30. Interactions between folate and aging for carcinogenesis
  31. The potential cocarcinogenic effect of vitamin B12 deficiency
  32. The vegetarian lifestyle and DNA methylation
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