Asymmetric dimethylarginine (ADMA) in vascular, renal and hepatic disease and the regulatory role of l-arginine on its metabolism

Molecular Genetics and Metabolism

Volumn 91, Issue 4, 2007, Pages 309-317

  Wilcken, David E L ^a   Sim, Ah Siew ^a   Wang, Jun ^a   Wang, Xing Li ^b  

^a UNIVERSITY OF NEW SOUTH WALES   (Australia)

^b BAYLOR COLLEGE OF MEDICINE   (United States)

Author keywords

Asymmetric dimethylarginine; Hepatic function; l Arginine; Nitric oxide; Renal function; Vascular risk

Indexed keywords

ARGININE; CITRULLINE; DIMETHYLARGININASE; HOMOCYSTEINE; N(G),N(G) DIMETHYLARGININE; NITRIC OXIDE SYNTHASE;

BIOAVAILABILITY; CARDIOVASCULAR RISK; DIET SUPPLEMENTATION; ENZYME ACTIVITY; HUMAN; INSULIN RESISTANCE; KIDNEY DISEASE; KIDNEY FUNCTION; LIVER DISEASE; LIVER FUNCTION; METABOLISM; OBESITY; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; SMOKING; VASCULAR DISEASE;

ARGININE; CITRULLINE; DIETARY SUPPLEMENTS; HEPATOCYTES; HOMOCYSTEINE; HUMANS; KIDNEY DISEASES; LIVER DISEASES; NITRIC OXIDE SYNTHASE; OBESITY; RISK FACTORS; VASCULAR DISEASES;

EID: 34447252828     PISSN: 10967192     EISSN: 10967206     Source Type: Journal    
DOI: 10.1016/j.ymgme.2007.04.017     Document Type: Review

References (81)

1. Vallance P., Leone A., Calver A., Collier J., and Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339 (1992) 572-575
2. Zoccali C., Mallamaci F., and Tripepi G. Traditional and emerging cardiovascular risk factors in end-stage renal disease. Kidney Int. Suppl. (2003) S105-S110
3. Fliser D., Kronenberg F., Kielstein J.T., Morath C., Bode-Boger S.M., Haller H., and Ritz E. Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study. J. Am. Soc. Nephrol. 16 (2005) 2456-2461
4. Boger R.H. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardiovasc. Res. 59 (2003) 824-833
5. Lentz S.R., Rodionov R.N., and Dayal S. Hyperhomocysteinemia, endothelial dysfunction, and cardiovascular risk: the potential role of ADMA. Atheroscler. Suppl. 4 (2003) 61-65
6. Lluch P., Torondel B., Medina P., Segarra G., Del Olmo J.A., Serra M.A., and Rodrigo J.M. Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis. J. Hepatol. 41 (2004) 55-59
7. Siroen M.P., Warle M.C., Teerlink T., Nijveldt R.J., Kuipers E.J., Metselaar H.J., Tilanus H.W., Kuik D.J., van der Sijp J.R., Meijer S., van der Hoven B., and van Leeuwen P.A. The transplanted liver graft is capable of clearing asymmetric dimethylarginine. Liver Transpl. 10 (2004) 1524-1530
8. Nijveldt R.J., Teerlink T., Siroen M.P., van der Hoven B., Prins H.A., Wiezer M.J., Meijer C., van der Sijp J.R., Cuesta M.A., Meijer S., and van Leeuwen P.A. Elevation of asymmetric dimethylarginine (ADMA) in patients developing hepatic failure after major hepatectomy. JPEN J. Parenter. Enteral. Nutr. 28 (2004) 382-387
9. Siroen M.P., Teerlink T., Nijveldt R.J., Prins H.A., Richir M.C., and van Leeuwen P.A. The clinical significance of asymmetric dimethylarginine. Annu. Rev. Nutr. 26 (2006) 203-228
10. Cooke J.P. Does ADMA cause endothelial dysfunction?. Arterioscler. Thromb. Vasc. Biol. 20 (2000) 2032-2037
11. Vallance P., and Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler. Thromb. Vasc. Biol. 24 (2004) 1023-1030
12. Leiper J.M., and Vallance P. The synthesis and metabolism of asymmetric dimethylarginine (ADMA). Eur. J. Clin. Pharmacol. 62 Suppl. 1 (2006) 33-38
13. Boger R.H., Sydow K., Borlak J., Thum T., Lenzen H., Schubert B., Tsikas D., and Bode-Boger S.M. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ. Res. 87 (2000) 99-105
14. Osanai T., Saitoh M., Sasaki S., Tomita H., Matsunaga T., and Okumura K. Effect of shear stress on asymmetric dimethylarginine release from vascular endothelial cells. Hypertension 42 (2003) 985-990
15. Leiper J.M., Santa Maria J., Chubb A., MacAllister R.J., Charles I.G., Whitley G.S., and Vallance P. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem. J. 343 Pt 1 (1999) 209-214
16. Closs E.I., Basha F.Z., Habermeier A., and Forstermann U. Interference of l-arginine analogues with l-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide 1 (1997) 65-73
17. Teerlink T. Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance. Clin. Chem. Lab. Med. 43 (2005) 1130-1138
18. Nijveldt R.J., Teerlink T., van Guldener C., Prins H.A., van Lambalgen A.A., Stehouwer C.D., Rauwerda J.A., and van Leeuwen P.A. Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia. Nephrol. Dial. Transplant. 18 (2003) 2542-2550
19. Nijveldt R.J., Teerlink T., Siroen M.P., van Lambalgen A.A., Rauwerda J.A., and van Leeuwen P.A. The liver is an important organ in the metabolism of asymmetrical dimethylarginine (ADMA). Clin. Nutr. 22 (2003) 17-22
20. Miyazaki H., Matsuoka H., Cooke J.P., Usui M., Ueda S., Okuda S., and Imaizumi T. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 99 (1999) 1141-1146
21. Kielstein J.T., Bode-Boger S.M., Frolich J.C., Haller H., and Boger R.H. Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease. Kidney Int. Suppl. 78 (2001) S9-S13
22. Lu T.M., Ding Y.A., Charng M.J., and Lin S.J. Asymmetrical dimethylarginine: a novel risk factor for coronary artery disease. Clin. Cardiol. 26 (2003) 458-464
23. Kielstein J.T., Boger R.H., Bode-Boger S.M., Frolich J.C., Haller H., Ritz E., and Fliser D. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J. Am. Soc. Nephrol. 13 (2002) 170-176
24. Mittermayer F., Krzyzanowska K., Exner M., Mlekusch W., Amighi J., Sabeti S., Minar E., Muller M., Wolzt M., and Schillinger M. Asymmetric dimethylarginine predicts major adverse cardiovascular events in patients with advanced peripheral artery disease. Arterioscler. Thromb. Vasc. Biol. 26 (2006) 2536-2540
25. Ziegler S., Mittermayer F., Plank C., Minar E., Wolzt M., and Schernthaner G.H. Homocyst(e)ine-lowering therapy does not affect plasma asymmetrical dimethylarginine concentrations in patients with peripheral artery disease. J. Clin. Endocrinol. Metab. 90 (2005) 2175-2178
26. Kielstein J.T., Impraim B., Simmel S., Bode-Boger S.M., Tsikas D., Frolich J.C., Hoeper M.M., Haller H., and Fliser D. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 109 (2004) 172-177
27. Wilcken D.E., Wang J., Sim A.S., Green K., and Wilcken B. Asymmetric dimethylarginine in homocystinuria due to cystathionine beta-synthase deficiency: relevance of renal function. J. Inherit. Metab. Dis. 29 (2006) 30-37
28. Wang J., Sim A.S., Wang X.L., Salonikas C., Naidoo D., and Wilcken D.E. Relations between plasma asymmetric dimethylarginine (ADMA) and risk factors for coronary disease. Atherosclerosis 184 (2006) 383-388
29. Cardounel A.J., Cui H., Samouilov A., Johnson W., Kearns P., Tsai A.-L., Berka V., and Zweier J.L. Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial no production and vascular function. J. Biol. Chem. 282 (2007) 879-887
30. Boger R.H., Maas R., Schulze F., and Schwedhelm E. Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality. Clin. Chem. Lab. Med. 43 (2005) 1124-1129
31. Mittermayer F., Schaller G., Pleiner J., Vychytil A., Sunder-Plassmann G., Horl W.H., and Wolzt M. Asymmetrical dimethylarginine plasma concentrations are related to basal nitric oxide release but not endothelium-dependent vasodilation of resistance arteries in peritoneal dialysis patients. J. Am. Soc. Nephrol. 16 (2005) 1832-1838
32. Heitzer T., Schlinzig T., Krohn K., Meinertz T., and Munzel T. Endothelial dysfunction oxidative stress and risk of cardiovascular events in patients with coronary artery disease. Circulation 104 (2001) 2673-2678
33. Neunteufl T., Heher S., Katzenschlager R., Wolfl G., Kostner K., Maurer G., and Weidinger F. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am. J. Cardiol. 86 (2000) 207-210
34. Perticone F., Ceravolo R., Pujia A., Ventura G., Iacopino S., Scozzafava A., Ferraro A., Chello M., Mastroroberto P., Verdecchia P., and Schillaci G. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 104 (2001) 191-196
35. Modena M.G., Bonetti L., Coppi F., Bursi F., and Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J. Am. Coll. Cardiol. 40 (2002) 505-510
36. Mudd S.H., Skovby F., Levy H.L., Pettigrew K.D., Wilcken B., Pyeritz R.E., Andria G., Boers G.H., Bromberg I.L., Cerone R., et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am. J. Hum. Genet. 37 (1985) 1-31
37. Nijveldt R.J., Siroen M.P., van der Hoven B., Teerlink T., Prins H.A., Girbes A.R., and van Leeuwen P.A. High plasma arginine concentrations in critically ill patients suffering from hepatic failure. Eur. J. Clin. Nutr. 58 (2004) 587-593
38. Ogawa T., Kimoto M., and Sasaoka K. Dimethylarginine:pyruvate aminotransferase in rats. Purification, properties, and identity with alanine:glyoxylate aminotransferase 2. J. Biol. Chem. 265 (1990) 20938-20945
39. Martin-Sanz P., Olmedilla L., Dulin E., Casado M., Callejas N.A., Perez-Pena J., Garutti I., Sanz J., Calleja J., Barrigon S., and Bosca L. Presence of methylated arginine derivatives in orthotopic human liver transplantation: relevance for liver function. Liver Transpl. 9 (2003) 40-48
40. Wang J., Sim A.S., Wang X.L., and Wilcken D.E. l-Arginine regulates asymmetric dimethylarginine metabolism by inhibiting dimethylarginine dimethylaminohydrolase activity in hepatic (HepG2) cells. Cell Mol. Life Sci. 63 (2006) 2838-2846
41. Ogawa T., Kimoto M., Watanabe H., and Sasaoka K. Metabolism of NG,NG-and NG,N'G-dimethylarginine in rats. Arch. Biochem. Biophys. 252 (1987) 526-537
42. Kielstein J.T., Boger R.H., Bode-Boger S.M., Schaffer J., Barbey M., Koch K.M., and Frolich J.C. Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J. Am. Soc. Nephrol. 10 (1999) 594-600
43. MacAllister R.J., Parry H., Kimoto M., Ogawa T., Russell R.J., Hodson H., Whitley G.S., and Vallance P. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br. J. Pharmacol. 119 (1996) 1533-1540
44. Ridker P.M., Brown N.J., Vaughan D.E., Harrison D.G., and Mehta J.L. Established and emerging plasma biomarkers in the prediction of first atherothrombotic events. Circulation 109 (2004) IV6-IV19
45. Yoo J.H., and Lee S.C. Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke. Atherosclerosis 158 (2001) 425-430
46. Stuhlinger M.C., Oka R.K., Graf E.E., Schmolzer I., Upson B.M., Kapoor O., Szuba A., Malinow M.R., Wascher T.C., Pachinger O., and Cooke J.P. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation 108 (2003) 933-938
47. Sydow K., Hornig B., Arakawa N., Bode-Boger S.M., Tsikas D., Munzel T., and Boger R.H. Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA. Vasc. Med. 9 (2004) 93-101
48. Sydow K., Schwedhelm E., Arakawa N., Bode-Boger S.M., Tsikas D., Hornig B., Frolich J.C., and Boger R.H. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of l-arginine and B vitamins. Cardiovasc. Res. 57 (2003) 244-252
49. Paroni R., Fermo I., Fiorina P., and Cighetti G. Determination of asymmetric and symmetric dimethylarginines in plasma of hyperhomocysteinemic subjects. Amino Acids 28 (2005) 389-394
50. Wilcken D.E., and Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment. J. Inherit. Metab. Dis. 20 (1997) 295-300
51. Yap S., Boers G.H., Wilcken B., Wilcken D.E., Brenton D.P., Lee P.J., Walter J.H., Howard P.M., and Naughten E.R. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler. Thromb. Vasc. Biol. 21 (2001) 2080-2085
52. Lu T.M., Ding Y.A., Leu H.B., Yin W.H., Sheu W.H., and Chu K.M. Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am. J. Cardiol. 94 (2004) 157-161
53. Annuk M., Zilmer M., and Fellstrom B. Endothelium-dependent vasodilation and oxidative stress in chronic renal failure: impact on cardiovascular disease. Kidney Int. Suppl. (2003) S50-S53
54. Stuhlinger M.C., Abbasi F., Chu J.W., Lamendola C., McLaughlin T.L., Cooke J.P., Reaven G.M., and Tsao P.S. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287 (2002) 1420-1426
55. Krzyzanowska K., Mittermayer F., Kopp H.P., Wolzt M., and Schernthaner G. Weight loss reduces circulating asymmetrical dimethylarginine concentrations in morbidly obese women. J. Clin. Endocrinol. Metab. 89 (2004) 6277-6281
56. Valkonen V.P., Laakso J., Paiva H., Lehtimaki T., Lakka T.A., Isomustajarvi M., Ruokonen I., Salonen J.T., and Laaksonen R. Asymmetrical dimethylarginine (ADMA) and risk of acute coronary events. Does statin treatment influence plasma ADMA levels?. Atheroscler. Suppl. 4 (2003) 19-22
57. McLaughlin T., Stuhlinger M., Lamendola C., Abbasi F., Bialek J., Reaven G.M., and Tsao P.S. Plasma asymmetric dimethylarginine concentrations are elevated in obese insulin-resistant women and fall with weight loss. J. Clin. Endocrinol. Metab. 91 (2006) 1896-1900
58. Eid H.M., Lyberg T., Arnesen H., and Seljeflot I. Insulin and adiponectin inhibit the TNFalpha-induced ADMA accumulation in human endothelial cells. The role of DDAH, atherosclerosis (2006)
59. O'Sullivan A.J., and Kelly J.J. Insulin resistance and protein catabolism in non-diabetic hemodialysis patients. Kidney Int. 71 (2007) 98-100
60. Konrad T., Zeuzem S., Toffolo G., Vicini P., Teuber G., Briem D., Lormann J., Lenz T., Herrmann G., Berger A., Cobelli C., and Usadel K. Severity of HCV-induced liver damage alters glucose homeostasis in noncirrhotic patients with chronic HCV infection. Digestion 62 (2000) 52-59
61. Zoccali C., Bode-Boger S., Mallamaci F., Benedetto F., Tripepi G., Malatino L., Cataliotti A., Bellanuova I., Fermo I., Frolich J., and Boger R. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358 (2001) 2113-2117
62. Schnabel R., Blankenberg S., Lubos E., Lackner K.J., Rupprecht H.J., Espinola-Klein C., Jachmann N., Post F., Peetz D., Bickel C., Cambien F., Tiret L., and Munzel T. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene study. Circ. Res. 97 (2005) e53-e59
63. Maas R., Schulze F., Baumert J., Lowel H., Hamraz K., Schwedhelm E., Koenig W., and Boger R.H. Asymmetric dimethylarginine, smoking, and risk of coronary heart disease in apparently healthy men: prospective analysis from the population-based monitoring of trends and determinants in cardiovascular disease/Kooperative Gesundheitsforschung in der Region Augsburg Study and Experimental Data. Clin. Chem. 53 (2007) 693-701
64. Boger R.H., Bode-Boger S.M., Szuba A., Tsao P.S., Chan J.R., Tangphao O., Blaschke T.F., and Cooke J.P. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 98 (1998) 1842-1847
65. Stuhlinger M.C., Tsao P.S., Her J.-H., Kimoto M., Balint R.F., and Cooke J.P. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 104 (2001) 2569-2575
66. Zhang W.Z., Venardos K., Chin-Dusting J., and Kaye D.M. Adverse effects of cigarette smoke on NO bioavailability: role of arginine metabolism and oxidative stress. Hypertension 48 (2006) 278-285
67. Dubois-Rande J.L., Zelinsky R., Roudot F., Chabrier P.E., Castaigne A., Geschwind H., and Adnot S. Effects of infusion of l-arginine into the left anterior descending coronary artery on acetylcholine-induced vasoconstriction of human atheromatous coronary arteries. Am. J. Cardiol. 70 (1992) 1269-1275
68. Tousoulis D., Davies G., Tentolouris C., Crake T., and Toutouzas P. Coronary stenosis dilatation induced by l-arginine. Lancet 349 (1997) 1812-1813
69. Creager M.A., Gallagher S.J., Girerd X.J., Coleman S.M., Dzau V.J., and Cooke J.P. l-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J. Clin. Invest. 90 (1992) 1248-1253
70. Preli R.B., Klein K.P., and Herrington D.M. Vascular effects of dietary l-arginine supplementation. Atherosclerosis 162 (2002) 1-15
71. Blum A., Hathaway L., Mincemoyer R., Schenke W.H., Kirby M., Csako G., Waclawiw M.A., Panza J.A., and Cannon III R.O. Effects of oral l-arginine on endothelium-dependent vasodilation and markers of inflammation in healthy postmenopausal women. J. Am. Coll. Cardiol. 35 (2000) 271-276
72. Blum A., Hathaway L., Mincemoyer R., Schenke W.H., Kirby M., Csako G., Waclawiw M.A., Panza J.A., and Cannon III R.O. Oral l-arginine in patients with coronary artery disease on medical management. Circulation 101 (2000) 2160-2164
73. Chin-Dusting J.P., Alexander C.T., Arnold P.J., Hodgson W.C., Lux A.S., and Jennings G.L. Effects of in vivo and in vitro l-arginine supplementation on healthy human vessels. J. Cardiovasc. Pharmacol. 28 (1996) 158-166
74. Chin-Dusting J.P., Kaye D.M., Lefkovits J., Wong J., Bergin P., and Jennings G.L. Dietary supplementation with l-arginine fails to restore endothelial function in forearm resistance arteries of patients with severe heart failure. J. Am. Coll. Cardiol. 27 (1996) 1207-1213
75. Schulman S.P., Becker L.C., Kass D.A., Champion H.C., Terrin M.L., Forman S., Ernst K.V., Kelemen M.D., Townsend S.N., Capriotti A., Hare J.M., and Gerstenblith G. l-Arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA 295 (2006) 58-64
76. Perticone F., Sciacqua A., Maio R., Perticone M., Maas R., Boger R.H., Tripepi G., Sesti G., and Zoccali C. Asymmetric dimethylarginine, l-arginine, and endothelial dysfunction in essential hypertension. J. Am. Coll. Cardiol. 46 (2005) 518-523
77. Chen J., Kuhlencordt P., Urano F., Ichinose H., Astern J., and Huang P.L. l-Arginine on atherosclerosis in ApoE knockout and ApoE/inducible NO synthase double-knockout mice. Arterioscler. Thromb. Vasc. Biol. 23 (2003) 97-103
78. Evans R.W., Fernstrom J.D., Thompson J., Morris Jr. S.M., and Kuller L.H. Biochemical responses of healthy subjects during dietary supplementation with l-arginine. J. Nutr. Biochem. 15 (2004) 534-539
79. Loscalzo J. What we know and don't know about l-arginine and NO. Circulation 101 (2000) 2126-2129
80. Loscalzo J. Adverse effects of supplemental l-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism?. Arterioscler. Thromb. Vasc. Biol. 23 (2003) 3-5
81. Eid H.M., Reims H., Arnesen H., Kjeldsen S.E., Lyberg T., and Seljeflot I. Decreased levels of asymmetric dimethylarginine during acute hyperinsulinemia. Metabolism 56 (2007) 464-469