Journal of Thrombosis and Thrombolysis

, Volume 27, Issue 2, pp 168–171 | Cite as

Asymmetric dimethylarginine and impaired cardiovascular healing

  • Giulio Coluzzi
  • Eleonora Santucci
  • Francesca Marzo
  • Felicita Andreotti
Article

Abstract

Asymmetric dimethylarginine (ADMA) typically accumulates in the plasma of patients with chronic renal failure. Moreover, its plasma levels are raised in the presence of virtually all of the traditional cardiovascular risk factors. ADMA inhibits the three isoforms of nitric oxide (NO) synthase, thereby blunting the known cardioprotective effects of NO. Through its NO inhibitor actions, ADMA also exerts pro-apoptotic effects and suppresses progenitor cell mobilization, differentiation and function. Among patients with ischemic heart disease, low progenitor cell bioavailability and kidney dysfunction are emerging as strong predictors of death and recurrent cardiovascular events. We propose that patients with ischemic heart disease, kidney dysfunction, and high risk factor burden exhibit adverse cardiovascular outcomes, at least in part, through ADMA-mediated NO depression, enhanced apoptotic signalling, and reduced progenitor cell bioavailability, with consequent blunting of cardiovascular healing. Further research into the mechanisms that regulate the NO/ADMA balance may advance our understanding of cardiovascular diseases.

Keywords

Asymmetric dimethylarginine Cardiovascular healing 

References

  1. 1.
    Ilhan N, Seckin D, Ilhan N, Ozbay Y (2007) Abnormal asymmetric dimethylarginine/nitric oxide balance in patients with documented coronary artery disease: relation to renal function and homocysteine. J Thromb Thrombolysis 23:205–211PubMedCrossRefGoogle Scholar
  2. 2.
    Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339:572–575PubMedCrossRefGoogle Scholar
  3. 3.
    Franzini L, Ardigò D, Dei Cas A, Valtuena S, Zavaroni I (2005) ADMA, oxidative stress and endothelial dysfunction: a vicious atherogenic loop? Heart Int 1:42–51Google Scholar
  4. 4.
    Kielstein JT, Impraim B, Simmel S, Bode-Böger SM, Tsikas D, Frölich JC, Hoeper MM, Haller H, Fliser D (2004) Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 109:172–177PubMedCrossRefGoogle Scholar
  5. 5.
    Böger RH, Zoccali C (2003) ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease. Atheroscler Suppl 4:23–28PubMedCrossRefGoogle Scholar
  6. 6.
    Schwedhelm E, Tan-Andresen J, Maas R, Riederer U, Schulze F, Böger RH (2005) Liquid chromatography-tandem mass spectrometry method for the analysis of asymmetric dimethylarginine in human plasma. Clin Chem 51:1268–1271PubMedCrossRefGoogle Scholar
  7. 7.
    Johannes J, Philip JS (2008) Asymmetrical dimethylarginine in renal disease: limits of variation or variation limits? Am J Nephrol 28:224–237CrossRefGoogle Scholar
  8. 8.
    Zoccali C, Bode-Böger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frölich J, Böger R (2001) Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358:2113–2117PubMedCrossRefGoogle Scholar
  9. 9.
    Andreotti F, Santucci E, Coluzzi G (2007) Contrast induced nephropathy and mortality: possible crucial role of asymmetric dimethylarginine. J Cardiovasc Med 8:1043CrossRefGoogle Scholar
  10. 10.
    Wang J, Sim AS, Wang XL, Salonika C, Naidoo D, Wilcken DE (2006) Relations between plasma asymmetric dimethylarginine (ADMA) and the risk factors for coronary disease. Atherosclerosis 184:383–388PubMedCrossRefGoogle Scholar
  11. 11.
    Altinova AE, Arslan M, Sepici-Dincel A, Akturk M, Altan N, Toruner FB (2007) Uncomplicated type 1 diabetes is associated with increased asymmetric dimethylarginine concentrations. J Clin Endocrinol Metab 92:1881–1885PubMedCrossRefGoogle Scholar
  12. 12.
    Miyazaki H, Matsuoka H, Cooke JP, Usui M; Ueda S, Okuda S, Imaizumi T (1999) Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 99:1141–1146PubMedGoogle Scholar
  13. 13.
    Antoniades C, Shirodaria C, Warrick N, Cai S, de Bono J, Lee J, Leenson P, Neubauer S, ratnatunga C, Pillai R, Refsum H, Channon KM (2006) 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels. Circulation 12:1193–1201CrossRefGoogle Scholar
  14. 14.
    Andreotti F, Becker RC (2005) Atherothrombotic disorders. New insights from hematology. Circulation 111:1855–1863PubMedCrossRefGoogle Scholar
  15. 15.
    Kissel CK, Lehmann R, Assmus B, Aicher A, Honold J, Fischer-Rasokat U, Heeschen C, Spyridopoulos I, Dimmeler S, Zeiher A (2007) Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with post infarction heart failure. J Am Coll Cardiol 49:2341–2349PubMedCrossRefGoogle Scholar
  16. 16.
    Jiang DJ, Jia SJ, Dai Z, Li YJ (2006) Asymmetric dimethylarginine induces apoptosis via p38 MAPK/caspase-3-dependent signalling pathways in endothelial cells. J Mol Cell Cardiol 40:529–539PubMedCrossRefGoogle Scholar
  17. 17.
    Werner N, Kosiol S, Schiegel T, Ahlers P, Walenta K, Link A, Böhm M, Nickenig G (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353:999–1007PubMedCrossRefGoogle Scholar
  18. 18.
    Aicher A, Zeiher AM, Dimmeler S (2005) Mobilizing endothelial progenitor cells. Hypertension 45:321–325PubMedCrossRefGoogle Scholar
  19. 19.
    Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593–600PubMedCrossRefGoogle Scholar
  20. 20.
    Andreotti F, Coluzzi G, Lavorgna A, Marzo F, Di Stasio E, Carrozza C, Zuppi C, Crea F (2007) Relation between haemoglobin concentrations and nitric oxide metabolites in ischemic heart disease. Heart 93:225–227Google Scholar
  21. 21.
    Thum T, Tsikas D, Stein S, Schultheiss M, Eigenthaler M, Anker SD, Poole-Wilson PA, Ertl G, Bauersachs J (2005) Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. J Am Coll Cardiol 146:1693–1701CrossRefGoogle Scholar
  22. 22.
    Wojciak-Stothard B, Torondel B, Tsang LY, Fleming I, Fisslthaler B, Leiper JM, Vallance P (2007) The ADMA/DDAH pathway is a critical regulator of endothelial cell motility. J Cell Sci 120:929–942PubMedCrossRefGoogle Scholar
  23. 23.
    Konishi H, Sydow K, Cooke JP (2007) Dimethylarginine dimethyaminohydrolase promotes endothelial repair after vascular injury. J Am Coll Cardiol 49:1099–1105PubMedCrossRefGoogle Scholar
  24. 24.
    Yuan Q, Jiang DJ, Chen QQ, Wang S, Xin HY, Deng HW, Li YJ (2007) Role of asymmetric dimethylarginine in homocysteine-induced apoptosis of vascular smooth muscle cells. Biochem Biophys Res Commun 356:880–885PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Giulio Coluzzi
    • 1
    • 2
    • 3
  • Eleonora Santucci
    • 1
  • Francesca Marzo
    • 1
  • Felicita Andreotti
    • 1
  1. 1.Department of Cardiovascular MedicineCatholic University Medical SchoolRomeItaly
  2. 2.NormaItaly
  3. 3.Department of Cardiovascular MedicineCatholic UniversityRomeItaly

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