1,334
Views
174
CrossRef citations to date
0
Altmetric
TRENDS IN MOLECULAR MEDICINE

Asymmetric dimethylarginine (ADMA): A novel risk marker in cardiovascular medicine and beyond

Pages 126-136 | Published online: 26 Aug 2009

References

  • Kakimoto Y., Akazawa S. Isolation and identification of NG,NG‐ and NG,N ´G‐dimethyl‐arginine, N‐epsilon‐mono‐, di‐, and trimethyllysine, and glucosylgalactosyl‐ and galactosyl‐delta‐hydroxylysine from human urine. J Biol Chem 1970; 245: 5751–8
  • McDermott J. R. Studies on the catabolism of NG‐methylarginine, NG, NG‐dimethylarginine and NG, NG ´‐dimethylarginine in the rabbit. Biochem J 1976; 154: 179–84
  • Rawal N., Rajpurohit R., Lischwe M. A., Williams K. R., Paik W. K., Kim S. Structural specifity of substrate for S‐adenosylmethionine:protein arginine N‐methyltransferases. Biochim Biophys Acta 1995; 1248: 11–18
  • Gary J. D., Clarke S. RNA and protein interactions modulated by protein arginine methylation. Prog Nucleic Acid Res Mol Biol 1998; 61: 65–131
  • Pawlak M. R., Banik‐Maiti S., Pietenpol J. A., Ruley H. E. Protein arginine methyltransferase I: substrate specificity and role in hnRNP assembly. J Cell Biochem 2002; 87: 394–407
  • Palmer R. M., Rees D. D., Ashton D. S., Moncada S. L‐arginine is the physiological precursor for the formation of nitric oxide in endothelium‐dependent relaxation. Biochem Biophys Res Commun 1988; 153: 1251–6
  • Rees D. D., Palmer R. M., Hodson H. F., Moncada S. A specific inhibitor of nitric oxide formation from L‐arginine attenuates endothelium‐dependent relaxation. Br J Pharmacol 1989; 96: 418–24
  • Vallance P., Leone A., Calver A., Collier J., Moncada S. Accumulation of an endogenous inhibitor of NO synthesis in chronic renal failure. Lancet 1992; 339: 572–5
  • Böger R. H., Zoccali C. ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end‐stage renal disease. Atherosclerosis Suppl 2003; 4: 23–8
  • Böger R. H., Bode‐Böger S. M., Frölich J. C. The L‐arginine – nitric oxide pathway: Role in atherosclerosis and therapeutic implications. Atherosclerosis 1996; 127: 1–11
  • Panza J. A., Quyyumi A. A., Brush J. E., Jr., Epstein S. E. Abnormal endothelium‐dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323: 22–7
  • Celermajer D. S., Sorensen K. E., Georgakopoulos D., et al. Cigarette smoking is associated with dose‐related and potentially reversible impairment of endothelium‐dependent dilation in healthy young adults. Circulation 1993; 88: 2149–55
  • Johnstone M. T., Creager S. J., Scales K. M., Cusco J. A., Lee B. K., Creager M. A. Impaired endothelium‐dependent vasodilation in patients with insulin‐dependent diabetes mellitus. Circulation 1993; 88: 2510–6
  • Tawakol A., Omland T., Gerhard M., Wu J. T., Creager M. A. Hyperhomocyst(e)inemia is associated with impaired endothelium‐dependent vasodilation in humans. Circulation 1997; 95: 1119–21
  • Böger R. H., Bode‐Böger S. M., Szuba A., et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998; 98: 1842–7
  • Hingorani A. D., Cross J., Kharbanda R. K., Mullen M. J., Bhagat K., Taylor M., Donald A. E., Palacios M., Griffin G. E., Deanfield J. E., MacAllister R. J., Vallance P. Acute systemic inflammation impairs endothelium‐dependent dilatation in humans. Circulation 2000; 102: 994–9
  • Böger R. H. The emerging role of ADMA as a novel cardiovascular risk factor. Cardiovasc Res 2003; 59: 824–33
  • Ogawa T., Kimoto M., Sasaoka K. Occurrence of a new enzyme catalysing the direct conversion of NG, NG‐dimethyl‐L‐arginine to L‐citrulline in rats. Biochem Biophys Res Commun 1987; 148: 671–7
  • Dayoub H., Achan V., Adimoolam S., Jacobi J., Stühlinger M. C., Wang B. Y., et al. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 2003; 108: 3042–7
  • Calver A., Collier J., Leone A., Moncada S., Vallance P. Effect of local intra‐arterial asymmetric dimethylarginine (ADMA) on the forearm arteriolar bed of healthy volunteers. J Hum Hypertens 1993; 7: 193–4
  • Achan V., Broadhead M., Malaki M., Whitley G., Leiper J., MacAllister R., et al. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolised by dimethylarginine dimethylaminohydolase. Arterioscler Thromb Vasc Biol 2003; 23: 1455–9
  • Kielstein J. T., Impraim B., Simmel S., Bode‐Boger S. M., Tsikas D., Frolich J. C., et al. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 2004; 109: 172–7
  • Chan J. R., Böger R. H., Bode‐Böger S. M., Tangphao O., Tsao P. S., Blaschke T. F., et al. Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans. Arterioscler Thromb Vasc Biol 2000; 20: 1040–6
  • Böger R. H., Bode‐Böger S. M., Thiele W., Junker W., Alexander K., Frölich J. C. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997; 95: 2068–74
  • Surdacki A., Nowicki M., Sandmann J., Tsikas D., Böger R. H., Bode‐Böger S. M., et al. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetrical dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol 1999; 33: 652–8
  • Kielstein J. T., Böger R. H., Bode‐Böger S. M., Schäffer J., Barbey M., Koch K. M., Frölich 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 1999; 10: 594–600
  • Schnog J. B., Teerlink T., van der Dijs F. P., Duits A. J., Muskiet F. A., CURAMA Study Group. Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell disease. Ann Hematol 2005; 84: 282–6
  • Gorenflo M., Zheng C., Werle E., Fiehn W., Ulmer H. E. Plasma levels of asymmetrical dimethyl‐L‐arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol 2001; 37: 489–92
  • Millatt L. J., Whitley G. S., Li D., Leiper J. M., Siragy H. M., Carey R. M., et al. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia‐induced pulmonary hypertension. Circulation 2003; 108: 1493–8
  • Kielstein J. T., Bode‐Böger S. M., Hesse G., Martens‐Lobenhöffer J., Takacs A., Fliser D., et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2005; 25: 1414–8
  • Miyazaki H., Matsuoka H., Cooke J. P. Endogenous nitric oxide synthase inhibitor. A novel marker of atherosclerosis. Circulation 1999; 99: 1141–6
  • Zoccali C., Benedetto F. A., Maas R., Mallamaci F., Tripepi G., Malatino L., et al. Asymmetric dimethylarginine (ADMA), C‐reactive protein, and carotid intima media‐thickness in end‐stage renal disease. J Am Soc Nephrol 2002; 13: 490–6
  • Valkonen V. P., Päivä H., Salonen J. T., Lakka T. A., Lehtimaki T., Laakso J., et al. Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 2001; 358: 2127–8
  • Zoccali C., Bode‐Böger S. M., Mallamaci F., Benedetto F. A., Tripepi G., Malatino L., et al. Asymmetric dimethylarginine (ADMA): An endogenous inhibitor of nitric oxide synthase predicts mortality in end‐stage renal disease (ESRD). Lancet 2001; 358: 2113–7
  • Nijveldt R. J., Teerlink T., van der Hoven B., Siroen M. P., Kuik D. J., Rauwerda J. A., 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
  • Lu T. M., Ding Y. A., Lin S. J., Lee W. S., Tai H. C. Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J 2003; 24: 1912–9
  • Krempl T. K., Maas R., Sydow K., Meinertz T., Böger R. H., Kähler J. Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events. Eur Heart J 2005; 26: 1846–51
  • Schnabel R., Blankenberg S., Lubos E., Lackner K. J., Rupprecht H. J., Espinola‐Klein C., et al. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res 2005; 97: e53–9
  • Cooke J. P. Asymmetrical dimethylarginine: the Über marker?. Circulation 2004; 109: 1813–8
  • Vallance P., Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 2004; 24: 1023–30
  • Sydow K., Münzel T. ADMA and oxidative stress. Atherosclerosis 2003; 4((Suppl. 4))41–51
  • Pritchard K. A., Jr., Groszek L., Smalley D. M., Sessa W. C., Wu M., Villalon P., et al. Native low‐density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion. Circ Res 1995; 77: 510–8
  • Closs E. I., Simon A., Vekony N., Tormann A. Plasma membrane transporters for arginine. J Nutr 2004; 134((10 Suppl.))2752S–9
  • Closs E. I., Basha F. Z., Habermeier A., Förstermann U. Interference of L‐arginine analogues with L‐arginine transport mediated by the y+ carrier hCAT‐2B. Nitric Oxide 1997; 1: 65–73
  • Bogle R. G., MacAllister R. J., Whitley G. S. J., Vallance P. Induction of NG‐monomethyl‐L‐arginine uptake: a mechanism for differential inhibiton of NO synthases?. Am J Physiol 1995; 269: C750–6
  • Böger R. H., Sydow K., Borlak J., Thum T., Lenzen H., Schubert B., et al. LDL Cholesterol upregulates synthesis of asymmetric dimethylarginine (ADMA) in human endothelial cells. Involvement of S‐adenosylmethionine‐dependent methyltransferases. Circ Res 2000; 87: 99–105
  • Moss M. B., Brunini T. M. C., Soares de Moura R., Novaes Malagris L. E., Roberts N. B., Ellory J. C., Mann G. E., Mendres Ribeiro A. C. Diminished L‐arginine bioavailability in hypertension. Clin Sci 2004; 107: 391–7
  • Goonasekera C. D., Rees D. D., Woolard P., Frend A., Shah V., Dillon M. J. Nitric oxide synthase inhibitors and hypertension in children and adolescents. J Hypertens 1997; 15: 901–9
  • Jang J. J., Ho H. K., Kwan H. H., Fajardo L. F., Cooke J. P. Angiogenesis is impaired by hypercholesterolemia: role of asymmetric dimethylarginine. Circulation 2000; 102: 1414–9
  • Jacobi J., Sydow K., von Degenfeld G., Zhang Y., Dayoub H., Wang B., et al. Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis. Circulation 2005; 111: 1431–8
  • Suda O., Tsutsui M., Morishita T., Tasaki H., Ueno S., Nakata S., et al. Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase‐deficient mice: involvement of renin‐angiotensin system and oxidative stress. Arterioscler Thromb Vasc Biol 2004; 24: 1682–8
  • Tsikas D., Rode I., Becker T., Nashan B., Klempnauer J., Frölich J. C. Elevated plasma and urine levels of ADMA and 15(S)‐8‐iso‐PGF2alpha in end‐stage liver disease. Hepatology 2003; 38: 1063–4
  • Siroen M. P., Warle M. C., Teerlink T., Nijveldt R. J., Kuipers E. J., Metselaar H. J., et al. The transplanted liver is capable of clearing asymmetric dimethylarginine. Liver transpl 2004; 10: 1524–30
  • Nijveldt R. J., Siroen M. P., Teerlink T., van Leeuwen P. A. Elimination of asymmetric dimethylarginine by the kidney and the liver: a link to the development of multiple organ failure?. J Nutr 2004; 134((10 Suppl.))2848S–52
  • Hermenegildo C., Medina P., Peiro M., Segarra G., Vila J. M., Ortega J., 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: 5636–40
  • Stühlinger M. C., Abbasi F., Chu J. W., Lamendola C., McLaughlin T. L., Cooke J. P., et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 2002; 287: 1420–6
  • Abbasi F., Asagami T., Cooke J. P., Lamendola C., McLaughlin T., Reaven G. M., et al. Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol 2001; 88: 1201–3
  • Pettersson A., Hedner T., Milsom I. Increased circulating concentrations of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, in preeclampsia. Acta Obstet Gynecol Scand 1998; 77: 808–13
  • Savvidou M. D., Hingorani A. D., Tsikas D., Frölich J. C., Vallance P., Nicolaides K. H. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre‐eclampsia. Lancet 2003; 361: 1511–7
  • Maas R., Serrano N., Schwedhelm E., Diaz L. A., Casas J. P., Böger R. H., et al. Plasma concentration of asymmetrical dimethylarginine (ADMA) in women with pre‐eclampsia from a high‐risk population. JAMA 2004; 291: 823–4
  • Abe T., Tohgi H., Murata T., Isobe C., Sato C. Reduction in asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in the cerebrospinal fluid during aging and in patients with Alzheimer's disease. Neurosci Lett 2001; 312: 177–9
  • Mulder C., Wahlund L. O., Blomberg M., de Jong S., van Kamp G. J., Scheltens P., et al. Alzheimer's disease is not associated with altered concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine in cerebrospinal fluid. J Neural Transm 2002; 109: 1203–8
  • Selley M. L. Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer's disease. Neurobiol Aging 2003; 24: 903–7
  • Kielstein J. T., Böger R. H., Bode‐Böger S. M., Martens‐Lobbenhöfer J., Lonnemann G., Frölich J. C., et al. Low dialysance of asymmetric dimethylarginine (ADMA) – in vivo and in vitro evidence of significant protein binding. Clin Nephrol 2004; 62: 295–300
  • Schwedhelm E. Quantification of ADMA: Analytical approaches. Vasc Med 2005; 10((Suppl. 1))S89–95
  • Albsmeier J., Schwedhelm E., Schulze F., Kastner M., Böger R. H. Determination of NG,NG‐dimethyl‐L‐arginine, an endogenous NO synthase inhibitor, by gas chromatography‐mass spectrometry. J Chromatogr B 2004; 809: 59–65
  • Schulze F., Wesemann R., Schwedhelm E., Sydow K., Albsmeier J., Cooke J. P., et al. Determination of ADMA using a novel ELISA assay. Clin Chem Lab Med 2004; 42: 1377–83
  • Böger RH. All about ADMA. www.allaboutadma.com (last accessed by the author on 10 November 2005).
  • Teerlink T. Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance. Clin Chem Lab Med 2005; 43: 1130–8
  • NHLBI Framingham Heart Study. Estimating Coronary Heart Disease (CHD) Risk Using Framingham Heart Study Prediction Score Sheets. December 2002. http://www.nhlbi.nih.gov/about/framingham/riskabs.htm (last accessed on 13 June 2005 by the author).
  • International Task Force for Prevention of Coronary Heart Disease, PROCAM Risk Calculator. 2004. http://www.chd‐taskforce.de/calculator/calculator.htm (last accessed on 13 June 2005 by the author).
  • European Society of Cardiology, CVD Prevention Score Risk Charts, 2004. http://www.escardio.org/initiatives/prevention/SCORE+Risk+Charts.htm (last accessed on 13 June 2005 by the author).
  • Schulze F., Maas R., Freese R., Schwedhelm E., Silberhorn L., Böger R. H. Determination of a reference value for N,N‐dimethyl‐L‐arginine in 500 subjects. Eur J Clin Invest 2005; 35: 622–6
  • Lee D. S., Vasan R. S. Novel markers for heart failure diagnosis and prognosis. Curr Opin Cardiol 2005; 20: 201–10
  • Mallamaci F., Tripepi G., Cutrupi S., Malatino L. S., Zoccali C. Prognostic value of combined use of biomarkers of inflammation, endothelial dysfunction, and myocardiopathy in patients with ESRD. Kidney Int 2005; 67: 2330–7
  • Böger R. H., Ron E. S. L‐Arginine improves vascular function by overcoming the deleterious effects of ADMA, a novel cardiovascular risk factor. Altern Med Rev 2005; 10: 14–23
  • Delles C., Schneider M. P., John S., Gekle M., Schmieder R. E. 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: 590–3
  • Ito A., Egashira K., Narishige T., Muramatsu K., Takeshita A. Angiotensin‐converting enzyme activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus. Circ J 2002; 66: 811–5
  • Böger R. H., Schwedhelm E., Maas R., Quispe‐Bravo S., Skamira C. ADMA and oxidative stress may relate to the progression of renal disease: Rationale and design of the VIVALDI study. Vasc Med 2005, In press
  • Asagami T., Abbasi F., Stuelinger M., Lamendola C., McLaughlin T., Cooke J. P., et al. Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes. Metabolism 2002; 51: 843–6
  • Lu T. M., Ding Y. A., Leu H. B., Yin W. H., Sheu W. H., Chu K. M. Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am J Cardiol 2004; 94: 157–61
  • Janatuinen T., Laakso J., Laaksonen R., Vesalainen R., Nuutila P., Lehtimaki T., et al. Plasma asymmetric dimethylarginine modifies the effect of pravastatin on myocardial blood flow in young adults. Vasc Med 2003 2003; 8: 185–9
  • Paiva H., Laakso J., Lehtimaki T., Isomustajarvi M., Ruokonen I., Laaksonen R. Effect of high‐dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors. J Cardiovasc Pharmacol 2003; 41: 219–22
  • Laufs U., La F., Plutzky J., Liao J. K. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97: 1129–35
  • Böger R. H. Asymmetric dimethylarginine (ADMA) modulates endothelial function – therapeutic implications. Vasc Med 2003; 8: 149–51
  • Böger G. I., Maas R., Schwedhelm E., Bierend A., Benndorf R., Kastner M., et al. Improvement of endothelium‐dependent vasodilation by simvastatin is potentiated by combination with L‐arginine sustained release in patients with elevated ADMA levels. [Abstract]. J Am Coll Cardiol 2004; Suppl: 525A

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.