Asymmetric dimethylarginine - a novel cardiovascular risk factor

Česká verzia

Authors: R. Široká; R. Cibulka; D. Rajdl; J. Racek
Authors place of work: Ústav klinické biochemie a hematologie Lékařské fakulty UK a FN Plzeň, přednosta prof. MUDr. Jaroslav Racek, DrSc.
Published in the journal: Vnitř Lék 2006; 52(3): 249-255
Category: Review

Summary

Understanding metabolism of nitric oxide (NO), signal molecule releasing from endothelial cells and influencing vascular tone, belongs to the most remarkable knowledge of last ten years. NO increases vascular tone, inhibits adhesion of monocytes and leukocytes to the vascular endothelium and reduces atherogenic process. Low NO level is one of pathogenic factors starting cardiovascular diseases. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of enzyme NO synthase, enzyme catalyzing NO production from arginine. This article gives a brief overview of contemporary state of the relation between ADMA and cardiovascular diseases. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilatation. In several prospective studies, ADMA evolved as a marker of cardiovascular risk. In the first chapters is described state of the art of biosynthesis, degradation and excretion of ADMA in connection with endothelial dysfunction, coronary artery disease, chronic heart failure, cardiovascular risk in haemodialysis patients, diabetes mellitus, hypertension, lipid metabolism disorders and intensive care unit treatment. Next chapters shortly summarize methods of ADMA detection and their applications. In conclusion clinical relevance of measurement of ADMA levels as a marker of endothelial dysfunction is discussed. Future research tasks of ADMA lead to prospective studies with different types of patients and also healthy population. Moreover ADMA is becoming a goal for pharmacotherapeutic intervention to improve endothelium-dependent vascular function in subjects with high ADMA levels.

Key words:
endothelial dysfunction - nitric oxide - asymmetric dimethylarginine - prognosis - cardiovascular disease

Zdroje

1. Racek J, Holeček V. Enzymy a volné radikály. Chem Listy 1999; 93: 774-780.

2. Kielstein JT, Frölich JC, Haller H et al. ADMA: an atherosclerotic disease mediating agent in patient with renal disease? Nephrol Dial Transplant 2001; 16: 1742-1745.

3. Miyazaki H, Matsuoka H, Cooke JP et al. Endogenous nitric oxide synthase inhibitor. A novel marker of atherosclerosis. Circulation 1999; 99: 1141-1146.

4. Vallance A, Leone A, Calver J et al. Accumulation of an endogenous inhibitor of NO synthesis in chronic renal failure. Lancet 1992; 339: 572-575.

5. Kurose R, Wolf MB, Grisham DN et al. Effects of an endogenous inhibitor of nitric oxide synthesis on postcapillary venules. Am J Physiol 1995; 268: H2224-H2231.

6. Faraci FM,. Brian JE, Heistad DD. Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol 1995; 269: H1522-H1527.

7. Segarra G, Medina P, Ballester RM et al. Effects of some guanidino compounds on human cerebral arteries. Stroke 1999; 30: 2206-2211.

8. Klatt P, Schmidt K, Uray G et al. Multiple catalytic functions of brain nitric oxide synthase. J Biol Chem 1994; 268: 14781-14787.

9. Vasquez-Vivar J, Kalyanaraman B, Martasek P et al. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 1998; 95: 9220-9225.

10. Pritchard KA, Groszek L, Smalley DM et al. Native low-density lipoprotein increases endothelial nitric oxide synthase generation of superoxide anion. Circ Res 1995; 77: 510-518.

11. Fickling SA, Leone AM, Nussey SS et al. Synthesis of NG,NG-dimethylarginine by human endothelial cells. Endothelium 1993; 1: 137-140.

12. MacAllister RJ, Fickling SA, Whitley GSJ et al. Metabolism of methylarginines by human vasculature: implications for the regulation of nitric oxide synthesis. Br J Pharmacol 1994; 112: 43-48.

13. Böger RH, Sydow K, Borlak J et al. Cholesterol upregulates synthesis of asymmetric dimethylarginine (ADMA) in human endothelial cells. Involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 2000; 87: 99-105.

14. Azuma H, Sato J, Hamasaki H et al. Accumulation of endogenous inhibitors for nitric oxide synthesis and decreased content of L-arginine in regenerated endothelial cells. Br J Pharmacol 1995; 115: 1001-1004.

15. MacAllister RJ, Parry H, Kimoto M et al. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 1996; 119: 1533-1540.

16. Ito S, Teak PS, Adimoolam S et al. Novel mechanism for endothelial dysfunction. Dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999; 99: 3092-3095.

17. Bogle RG, MacAllister RJ, Whitley GSJ et al. Induction of NG-monomethyl-arginine uptake: a mechanism for differential inhibition of NO synthases? Am J Physiol 1995; 269: C750-C756.

18. Kielstein JT, Bode-Böger SM, Frölich JC et al. Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease. Kidney Int 2001; 78, Suppl: S9-S13.

19. MacAllister RJ, Rambausek MH, Vallance P et al. Concentration of dimethyl-arginine in the plasma of patients with end-stage renal failure. Nephrol Dial Transplant 1996; 11: 2449-2452.

20. Kielstein JT, Böger RH, Bode-Böger SM et al. Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol 1999; 10: 594-600.

21. Gross JM, Donald AE, Vallance P et al. Dialysis improves endothelial function in humans. Nephrol Dial Transplant 2001; 16: 823-1829.

22. Ogawa T, Kimoto M, Sasanka K. Occurrence of a new enzyme catalysing the direct conversion of NG,NG-dimethyl- arginine to-citrulline in rats. Biochem Biophys Res Commun 1987; 148: 671-677.

23. Leiper JM, Santa Maria J, Chubb A et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 1999; 343: 209-214.

24. Stühlinger MC, Tsao PS, Her JH et al. Homocysteine impairs the nitric oxide synthase pathway. Role of asymmetric dimethylarginine. Circulation 2001; 104: 2569-2575.

25. Leiper J, Murray-Rust J, Macdonald N et al. S-Nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci 2002; 99: 13527-13532.

26. Achan V, Tran CT, Strigoni F et al. All-trans-retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. Circ Res 2002; 90: 764-769.

27. Böger RH, Bode-Böger SM, Szuba A et al. Asymmetric dimethylarginine: a novel risk factor for endothelial dysfunction. Its role in hypercholesterolemia. Circulation 1998; 98: 1842-1847.

28. Böger RH, Bode-Böger SM, Thiele W et al. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997; 95: 2068-2074.

29. Böger RH, Lenzen H, Hanefeld C et al. Asymmetric dimethylarginine: an endogenous inhibitor of NO synthase is a predictor of the risk for coronary heart disease - Result of multicenter CARDIAC study. Circulation 2003; 108: IV-256 52.

30. Böger RH, Zoccali C. ADMA: A novel risk factor that explains excess cardiovascular event rate in patient with end-stage renal disease. Atherosclerosis Suppl 2003; 4: 23-28.

31. Široká R, Trefil L, Rajdl D et al. Asymmetric dimethylarginine, homocysteine and renal function - is there a relation? Clin Chem Lab Med 2005, 43; 1147-1150.

32. Široká R, Trefil L, Rajdl D et al. Asymetrický dimethylarginin, homocystein a funkce ledvin. KBM 2005; in press.

33. Zoccali C, Bode-Böger SM, Mallamaci F et al. Asymmetric dimethylarginine (ADMA): an endogenous inhibitor of nitric oxide synthase predicts mortality in end-stage renal disease (ESRD). Lancet 2001; 358: 2113-2117.

34. Hornig B, Arakawa N, Böger RH et al. Plasma levels of ADMA are increased and inversely related to endothelium-mediated vasodilatation in patients with chronic heart failure: a new predictor of endothelial dysfunction? Circulation 1998; 98(Suppl): I-318.

35. Zoccali C, Mallamaci F, Maas R et al. Left ventricular hypertrophy, cardiac remodelling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int 2002; 62: 339-345.

36. Abbasi F, Asagmi T, Cooke JP et al. Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol 2001; 88: 1201-1203.

37. Fard A, Tuck CH, Donis JA et al. Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 2000; 20: 2039-2044.

38. Stühlinger M, Abbasi F, Chu et JW et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. J Am Med Assoc 2002; 287: 420-426.

39. Lin KY, Ito A, Asagami T et al. Impaired nitric oxide synthase pathway in diabetes mellitus. Role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 2002; 106: 987-992.

40. Ito A, Egashira K, Narishige T et al. Angiotensin-converting enzyme activity is involvedin the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus. Circ J 2002; 66: 811-815.

41. Rainer H, Böger RH. Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Explains the ”L-Arginine Paradox” and Acts as a Novel Cardiovascular Risk Factor 1,2. Nitric Oxide 2004; 11: 1-8.

42. Lundman P, Eriksson, MJ, Stühlinger M et al. Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. J Am Coll Cardiol 2001; 38: 111-116.

43. Nijveldt RJ, Teerlink T, Van Der Hoven B et al. Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality. Clin Nutr 2003; 22: 23-30.

44. Nijveldt RJ, Teerlink T, Siroen MP et al. The liver is an important organ in the

metabolism of asymmetrical dimethylarginine (ADMA). Clin Nutr 2003; 22: 17-22.

45. Tsikas D, Rode I, Becker T et al. Elevated plasma and urine levels of ADMA and 15(S)-8-iso-PGF2alpha in end-stage liver disease. Hepatology 2003; 38: 1063-1064.

46. Teerlink T, Nijveldt RJ, de Jong S et al. Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem 2002; 303: 131-137.

47. Široká R, Racek J, Filipovský J. Asymetrický dimethylarginin (ADMA). Klin Biochem Metab 2005; 13:131-134.

48. Schulze F, Wesemann R, Schwedhelm E et al. Determination of asymmetric dimethylarginine (ADMA) by a novel ELISA assay. Clin Chem Lab Med 2004; 42: 1377-1383.

49. Böger RH, Bode-Boger SM, Thiele W et al. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol 1998; 32: 1336-1344.

50. Rector TS, Bank AJ, Kuklen KA et al. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation 1996; 93: 2135-2141.

51. Ceremuzynksi L, Chamiec T, Herbacynska-Cedro K. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol 1997; 80: 331-333.

52. Maxwell AJ, Anderson BE, Cooke JP. Nutritional therapy for peripheral arterial disease: a double-blind, placebo-controlled, randomized trial of Heart Bar. Vasc Med 2000; 5: 11-19.

53. Tousoulis D, Davies GJ, Tentolouris C et al. Effects of L-arginine on flow mediated dilatation induced by atrial pacing in diseased epicardial coronary arteries. Heart 2003; 89: 531-534.

54. Delles C, Schneider MP, John S et al. Angiotensin converting enzyme inhibition and angiotensin II AT1-receptor blockade reduce the levels of asymmetrical N(G), N(G)-dimethylarginine in human essential hypertension. Am J Hypertens 2002;15: 590-593.

55. Holven KB, Haugstad TS, Holm T et al. Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects. Br J Nutr 2003; 89: 359-363.

56. Valkonen VP, Laakso J, Paiva H et al. Asymmetrical dimethylarginine (ADMA) and risk of acute coronary events. Does statin treatment influence plasma ADMA levels?

Atheroscler Suppl 2003; 4: 19-22.

57. Lu TM, Ding YA, Leu HB et al. Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am J Cardiol 2004; 94: 157-161.

58. Jiang JL, Jiang DJ, Tang YH et al. Effect of simvastatin on endothelium-dependent vaso-relaxation and endogenous nitric oxide synthase inhibitor. Acta Pharmacol Sin 2004; 25: 893-901.

59. Sydow K, Munzel T. ADMA and oxidative stress. Atheroscler Suppl 2003; 4: 41-51.

60. Krzyzanowska K, Mittermayer F, Kopp HP et al. Weight loss reduces circulating asymmetrical dimethylarginine concentrations in morbidly obese women. J Clin Endocrinol Metab 2004; 89: 6277-6281.

61. Surdacki A, Nowicki M, Sandmann J et al. Effects of acute euglycemic hyperinsulinemia on urinary nitrite/nitrate excretion and plasma endothelin-1 levels in men with essential hypertension and normotensive controls. Metabolism 1999; 48: 887-891.

62. Goonasekera CD, Shah V, Rees DD et al. Vascular endothelial cell activation associated with increased plasma asymmetric dimethyl arginine in children and young adults with hypertension: a basis for atheroma? Blood Press 2000; 9: 16-21.

63. Holden DP, Fickling SA, Whitley GS et al. Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol 1998; 178: 551-556.

64. Savvidou MD, Hingorani AD, Tsikas D et al. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 2003; 361: 1511-1517.

65. Gorenflo M, Zheng C, Werle E et al. Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol 2001; 37: 489-492.

66. Sydow K, Hornig B, Arakawa N et al. Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA.Vasc Med 2004; 9: 93-101.

67. Yoo JH, Lee SC. Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke. Atherosclerosis 2001; 158: 425-430.

68. Usui M, Matsuoka H, Miyazaki H et al. Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci 1998; 62: 2425-2430.

69. Hermenegildo C, Medina P, Peiro M et al. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients. J Clin Endocrinol Metab 2002; 87: 5636-5640.