Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. Like many other cardiovascular risk factors, hyperhomocysteinemia produces endothelial dysfunction due to impaired bioavailability of endothelium-derived nitric oxide (NO). The molecular mechanisms responsible for decreased NO bioavailabil ity in hyperhomocysteinemia are incompletely understood, but emerging evidence suggests that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may be a key mediator. Homocysteine is produced during the synthesis of ADMA and can alter ADMA metabolism by inhibiting dimethylarginine dimethy laminohydrolase (DDAH). Several animal and clinical studies have demonstrated a strong association between plasma total homocysteine, plasma ADMA, and endothelial dysfunction. These observations suggest a model in which elevation of ADMA may be a unifying mechanism for endothelial dysfunction during hyper homocysteinemia. The recent development of transgenic mice with altered ADMA metabolism should provide further mechanistic insights into the role of ADMA in hyperhomocysteinemia.
Selhub J.Homocysteine metabolism. Annu Rev Med1999 ; 19: 217-46.
2.
Mudd SH, Finkelstein JD, Refsum H. et al. Homocysteine and its disulfide derivatives: a suggested consensus terminology. Arterioscler Thromb Vasc Biol2000; 20: 1704-706.
3.
Lentz SR, Haynes WGHomocysteine: is it a clinically important cardiovascular risk factor?Cleve Clin J Med2004; 71: 729-34.
4.
McCully KSVascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol1969; 56: 111-28.
5.
Homocysteine Studies Collaboration.Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis . JAMA2002;288:2015-22.
6.
Wald DS, Law M., Morris JKHomocysteine and cardiovascular disease: evidence on causality from a meta-analysis . BMJ2002; 325: 1202.
7.
Clarke R., Armitage J.Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements. Semin Thromb Hemost2000; 26: 341-48.
8.
Sengupta S., Wehbe C., Majors AK, Ketterer ME, DiBello PM, Jacobsen DWRelative roles of albumin and ceruloplasmin in the formation of homocysteine, homocysteine-cysteine mixed disulfide and cystine in circulation. J Biol Chem2001; 276: 46896-904.
9.
Lentz SRHomocysteine and cardiovascular physiology. In: Carmel R, Jacobsen DW, eds. Homocysteine in health and disease. Cambridge : Cambridge University Press, 2001 : 441-50.
10.
Watanabe M. , Osada J., Aratani Y. et al. Mice deficient in cystathionine β-synthase: animal models for mild and severe homo-cyst(e)inemia . Proc Natl Acad Sci U S A1995; 92: 1585-89.
11.
Chen Z., Karaplis AC, Ackerman SL et al. Mice deficient in methylene tetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet2001; 10: 433-43.
12.
Swanson DA, Liu ML, Baker PJ et al. Targeted disruption of the methionine synthase gene in mice . Mol Cell Biol2001; 21: 1058-65.
13.
Cai H., Harrison DGEndothelial dysfunction in cardiovascular diseases: the role of oxidant stress . Circ Res2000; 87: 840-44.
14.
Schachinger V., Britten MB, Zeiher AMPrognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation2000; 101: 1899-906.
15.
Lentz SR, Sobey CG, Piegors DJ et al. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia . J Clin Invest1996; 98: 24-29.
16.
Quere I., Hillairebuys D., Brunschwig C. et al. Effects of homocysteine on acetylcholine- and adenosine-induced vasodilatation of pancreatic vascular bed in rats. Br J Pharmacol1997; 122: 351-57.
17.
Zhang F., Slungaard A., Vercellotti GM, ladecola C.Superoxide-dependent cerebrovascular effects of homocysteine. Am J Physiol1998; 274: R1704-11.
18.
Ungvari Z., Pacher P., Rischak K., Szollar L., Koller A.Dysfunction of nitric oxide mediation in isolated rat arterioles with methionine diet-induced hyperhomocysteinemia. Arterioscler Thromb Vasc Biol1999; 19: 1899-904.
19.
Lentz SR, Erger RA, Dayal S. et al. Folate dependence of hyperhomocysteinemia and endothelial dysfunction in cystathionine β-synthase-deficient mice. Am J Physiol2000; 278: H970-75.
20.
Eberhardt RT , Forgione MA, Cap A. et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest2000; 106: 483-91.
21.
Dayal S., Bottiglieri T., Arning E. et al. Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine β-synthase-deficient mice. Circ Res2001; 88: 1203-209.
22.
Dayal S., Arning E., Bottiglieri T. et al. Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke2004; 35: 1957-62.
23.
Chambers JC , McGregor A., Jean-Marie J., Kooner JSAcute hyperhomocysteinemia and endothelial dysfunction. Lancet1998; 351: 36-37.
24.
Bellamy MF, Mcdowell Ifw, Ramsey MW et al. Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation1998; 98: 1848-52.
25.
Chambers JC , McGregor A., Jean-Marie J., Obeid OA, Kooner JSDemonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia . An effect reversible with vitamin C therapy. Circulation1999; 99: 1156-60.
26.
Usui M., Matsuoka H., Miyazaki H., Ueda S., Okuda S., Imaizumi T.Endothelial dysfunction by acute hyperhomocyst(e)inemia: restoration by folic acid. Clin Sci1999; 96: 235-39.
27.
Kanani PM, Sinkey CA, Browning RL, Allaman M., Knapp HR, Haynes WGRole of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation1999; 100: 1161-68.
28.
Raghuveer G. , Sinkey CA, Chenard C., Stumbo P., Haynes WGEffect of vitamin E on resistance vessel endothelial dysfunction induced by methionine. Am J Cardiol2001; 88: 285-90.
29.
Devlin AM, Arning E., Bottiglieri T., Faraci FM, Rozen R., Lentz SREffect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice. Blood2004; 103: 2624-29.
30.
Dayal S., Devlin AM, McCaw RB et al. Cerebral vascular dysfunction in methionine synthase-deficient mice [Abstract]. Blood2004; 104: 2617.
31.
Weiss N., Heydrick S., Zhang YY, Bierl C., Cap A., Loscalzo J.Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine beta-synthase-deficient mice. Arterioscler Thromb Vasc Biol2002; 22: 34-41.
32.
Virdis A., Iglarz M., Neves MF et al. Effect of hyperhomocysteinemia and hypertension on endothelial function in methylenetetrahydrofolate reductase-deficient mice. Arterioscler Thromb Vasc Biol2003; 23: 1352-57.
33.
Faraci FMHyperhomocysteinemia: a million ways to lose control. Arterioscler Thromb Vasc Biol2003; 23: 371-73.
34.
Ungvari Z., Csiszar A., Edwards JG et al. Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis factor-alpha, NAD(P)H oxidase, and inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol2003; 23: 418-24.
35.
Weiss N., Zhang YY, Heydrick S., Bierl C., Loscalzo J.Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction. Proc Natl Acad Sci U S A2001; 98: 12503-508.
36.
Dayal S., Brown KL, Weydert CJ et al. Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to endothelial dysfunction. Arterioscler Thromb Vasc Biol2002; 22: 1996-2002.
37.
Bagi Z., Cseko C., Toth E., Koller A.Oxidative stress-induced dysregulation of arteriolar wall shear stress and blood pressure in hyperhomocysteinemia is prevented by chronic vitamin C treatment. Am J Physiol Heart CircPhysiol2003; 285: H2277-83.
38.
Böger RHThe emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardiovasc Res2003; 59: 824-33.
39.
Heydrick SJ , Weiss N., Thomas SR et al. L-homocysteine and L-homocystine stereospecifically induce endothelial nitric oxide synthase-dependent lipid peroxidation in endothelial cells. Free Radic Biol Med2004; 36: 632-40.
40.
Lentz SR, Sadler JEInhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest1991; 88: 1906-14.
41.
Lentz SR, Sadler JEHomocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. Blood1993; 81: 683-89.
42.
Austin RC, Lentz SR, Werstuck GHRole of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ2004; 11: S56-S64.
43.
Zhang C., Cai Y., Adachi MT et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. J Biol Chem2001; 276: 35867-74.
44.
Böger RH, Bode-Böger SM, Szuba A. et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction - its role in hypercholesterolemia. Circulation1998; 98: 1842-47.
45.
Ghosh SK, Paik WK, Kim S.Purification and molecular identification of two protein methylases I from calf brain. Myelin basic protein- and histone-specific enzyme. J Biol Chem1988; 263: 19024-33.
46.
Rawal N., Rajpurohit R, Paik WK, Kim S. Purification and characterization of S-adenosylmethionine-protein-arginine N-methyltransferase from rat liver. Biochem J1994; 300: 483-89.
47.
McDermott JRStudies on the catabolism of NG-methylarginine, NG, NG-dimethylarginine and NG, NG-dimethylarginine in the rabbit. Biochem J1976; 154: 179-84.
48.
Böger RH, Bode-Böger SM, Sydow K., Heistad DD, Lentz SRPlasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arterioscler Thromb Vasc Biol2000; 20: 1557-64.
49.
Böger RH, Lentz SR, Bode-Böger SM, Knapp HR, Haynes WGElevation of asymmetric dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inemia in humans. Clin Sci2001; 100: 161-67.
50.
Stühlinger MC, Oka RK, Graf EE et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation2003; 108: 933-38.
51.
Böger RH, Sydow K., Borlak J. et al. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res2000; 87: 99-105.
52.
Stühlinger MC, Tsao PS, Her JH, Kimoto M., Balint RF, Cooke JPHomocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation2001; 104: 2569-75 .
53.
Selley MLHomocysteine increases the production of asymmetric dimethylarginine in cultured neurons. J Neurosci Res2004; 77: 90-93.
54.
Holven KB, Haugstad TS, Holm T., Aukrust P., Ose L., Nenseter MSFolic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects. Br J Nutr2003; 89: 359-63.
55.
Sydow K., Schwedhelm E., Arakawa N. et al. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovasc Res2003; 57: 244-52.
56.
Yoo JH, Lee SCElevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke. Atherosclerosis2001; 158: 425-30.
57.
Jonasson TF , Hedner T., Hultberg B., Ohlin H.Hyperhomocysteinaemia is not associated with increased levels of asymmetric dimethylarginine in patients with ischaemic heart disease. Eur J Clin Invest2003; 33: 543-49.
58.
Vallance P.The asymmetrical dimethylarginine/dimethylarginine dimethylaminohydrolase pathway in the regulation of nitric oxide production . Clin Sci2001; 100: 159-60.
59.
Kuzkaya N., Weissmann N., Harrison DG, Dikalov S.Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase . J Biol Chem2003; 278: 22546-54.
60.
Wanby P., Brattstrom L., Brudin L., Hultberg B., Teerlink T.Asymmetric dimethylarginine and total homocysteine in plasma after oral methionine loading. Scand J Clin Lab Invest2003 ; 63: 347-53.
61.
Clarke R.Design of clinical trials to test the homocysteine hypothesis of vascular disease. In: Carmel R, Jacobsen DW eds. Homocysteine in health and disease. Cambridge: Cambridge University Press, 2001: 477-84.
62.
Dayoub H., Achan V., Adimoolam S. et al. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation2003; 108: 3042-47.
