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Amino Acids

, Volume 47, Issue 9, pp 1741–1750 | Cite as

Homoarginine in the shadow of asymmetric dimethylarginine: from nitric oxide to cardiovascular disease

  • Nikolaos Papageorgiou
  • Emmanuel Androulakis
  • Spyridon Papaioannou
  • Charalambos Antoniades
  • Dimitris TousoulisEmail author
Review Article
Part of the following topical collections:
  1. Homoarginine, Arginine and Relatives

Abstract

It is well known that the endothelium maintains the vascular homeostasis. Importantly, endothelial dysfunction is regarded as a key early step in the development of atherosclerosis. Back in the early 1990s, it was found that asymmetric dimethylarginine (ADMA), an arginine metabolite derived from l-arginine (Arg) residues in proteins by asymmetric dimethylation on its guanidine group, is an endogenous inhibitor of nitric oxide (NO) synthase (NOS) isoforms. Inhibition of NO synthesis from Arg by the endothelial NOS isoform (eNOS) leads to endothelial dysfunction. Due to this action, ADMA participates in the pathophysiology of atherosclerosis and potentially contributes to cardiovascular events. Nowadays, homoarginine (hArg) is considered as a new key player in atherogenesis. hArg is a non-essential, non-proteinogenic amino acid which is synthesized from Arg by arginine:glycine amidinotransferase (AGAT). hArg is structurally related to Arg; formally, hArg is by one methylene (CH2) group longer than Arg, and may serve as a substrate for NOS, thus contributing to NO synthesis. For several decades, the pathophysiological role of hArg has been entirely unknown. hArg has been in the shadow of ADMA. Clinical studies have sought to investigate the relationship between circulating hArg levels and human disease states as well as cardiovascular prognosis. Recent studies indicate that hArg is actively involved in the vascular homeostasis, yet the underlying mechanisms are incompletely understood. In this article, we review the available literature regarding the role of ADMA and hArg in endothelial dysfunction and in cardiovascular disease as well as the possible associations between these endogenous Arg derivatives.

Keywords

Asymmetric dimethylarginine l-Homoarginine Endothelial dysfunction Cardiovascular disease 

Abbreviations

ADMA

Asymmetric dimethylarginine

AGAT

Arginineglycine amidinotransferase

CAD

Coronary artery disease

CVD

Cardiovascular disease

DDAH

Dimethylarginine dimethylaminohydrolase

FMD

Flow-mediated dilatation

GAMT

Guanidinoacetate methyltransferase

hArg

Homoarginine

IMT

Intima-media thickness

MMA

Monomethylarginine

NO

Nitric oxide

NOS

NO synthase

eNOS

Endothelial nitric oxide synthase

nNOS

Neuronal nitric oxide synthase

PCI

Percutaneous coronary intervention

PRMTs

Protein arginine N-methyltransferases

ROS

Reactive oxygen species

SDMA

Symmetric dimethylarginine

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

This article does not contain any studies with human subjects or animals.

References

  1. Achan V, Broadhead M, Malaki M et al (2003) Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol 23:1455–1459CrossRefPubMedGoogle Scholar
  2. Antoniades C, Tousoulis D, Marinou K et al (2006) Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines. Am J Clin Nutr 84:781–788PubMedGoogle Scholar
  3. Atzler D, Rosenberg M, Anderssohn M et al (2013) Homoarginine–an independent marker of mortality in heart failure. Int J Cardiol 168:4907–4909CrossRefPubMedGoogle Scholar
  4. Atzler D, Gore MO, Ayers CR et al (2014) Homoarginine and cardiovascular outcome in the population-based Dallas Heart Study. Arterioscler Thromb Vasc Biol 34:2501–2507CrossRefPubMedGoogle Scholar
  5. Böger RH (2003) The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardiovasc Res 59:824–833CrossRefPubMedGoogle Scholar
  6. Böger RH (2005) Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials. Vasc Med 10(Suppl 1):S19–S25CrossRefPubMedGoogle Scholar
  7. Böger RH, Sydow K, Borlak J et al (2000) LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 87:99–105CrossRefPubMedGoogle Scholar
  8. Bonetti PO, Lerman LO, Lerman A (2003) Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 23:168–175CrossRefPubMedGoogle Scholar
  9. Bulau P, Zakrzewicz D, Kitowska K et al (2007) Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA. Am J Physiol Lung Cell Mol Physiol 2007(292):L18–L24Google Scholar
  10. Cavusoglu E, Ruwende C, Chopra V et al (2009) Relationship of baseline plasma ADMA levels to cardiovascular outcomes at 2 years in men with acute coronary syndrome referred for coronary angiography. Coron Artery Dis 20:112–117CrossRefPubMedGoogle Scholar
  11. Chen PY, Sanders PW (1993) Role of nitric oxide synthesis in salt-sensitive hypertension in Dahl/Rapp rats. Hypertension 22:812–818CrossRefPubMedGoogle Scholar
  12. Choe CU, Atzler D, Wild PS et al (2013) Homoarginine levels are regulated by l-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. Circulation 128:1451–1461CrossRefPubMedGoogle Scholar
  13. Davids M, Ndika JD, Salomons GS, Blom HJ, Teerlink T (2012) Promiscuous activity of arginine:glycine amidinotransferase is responsible for the synthesis of the novel cardiovascular risk factor homoarginine. FEBS Lett 586:3653–3657CrossRefPubMedGoogle Scholar
  14. Drechsler C, Kollerits B, Meinitzer A et al (2013) Homoarginine and progression of chronic kidney disease: results from the Mild to Moderate Kidney Disease Study. PLoS One 8:e63560PubMedCentralCrossRefPubMedGoogle Scholar
  15. Fard A, Tuck CH, Donis JA et al (2000) 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 20:2039–2044CrossRefPubMedGoogle Scholar
  16. Fujiwara N, Osanai T, Kamada T et al (2000) Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension:modulation of nitric oxide synthesis by salt intake. Circulation 101:856–861CrossRefPubMedGoogle Scholar
  17. Furuki K, Adachi H, Matsuoka H et al (2007) Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima-media thickness of the carotid artery: an epidemiological study. Atherosclerosis 191:206–210CrossRefPubMedGoogle Scholar
  18. Guzik TJ, Sadowski J, Kapelak B et al (2004) Systemic regulation of vascular NAD(P)H oxidase activity and nox isoform expression in human arteries and veins. Arterioscler Thromb Vasc Biol 24:1614–1620CrossRefPubMedGoogle Scholar
  19. Hori T, Matsubara T, Ishibashi T et al (2003) Significance of asymmetric dimethylarginine (ADMA) concentrations during coronary circulation in patients with vasospastic angina. Circ J 67:305–311CrossRefPubMedGoogle Scholar
  20. Huynh NN, Chin-Dusting J (2006) Amino acids, arginase and nitric oxide in vascular health. Clin Exp Pharmacol Physiol 33:1–8CrossRefPubMedGoogle Scholar
  21. Ito A, Tsao PS, Adimoolam S et al (1999) Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 99:3092–3095CrossRefPubMedGoogle Scholar
  22. Jaźwińska-Kozuba A, Martens-Lobenhoffer J, Kruszelnicka O et al (2013) Opposite associations of plasma homoarginine and ornithine with arginine in healthy children and adolescents. Int J Mol Sci 14:21819–21832CrossRefPubMedGoogle Scholar
  23. Juonala M, Viikari JS, Alfthan G et al (2007) Brachial artery flowmediated dilation and asymmetrical dimethylarginine in the cardiovascular risk in young Finns study. Circulation 116:1367–1373CrossRefPubMedGoogle Scholar
  24. Kaito K, Otsubo H, Usui N et al (2005) Platelet size deviation width, platelet large cell ratio, and mean platelet volume have sufficient sensitivity and specificity in the diagnosis of immune thrombocytopenia. Br J Haematol 128:698–702CrossRefPubMedGoogle Scholar
  25. Kayacelebi AA, Pham VV, Willers J et al (2014a) Plasma homoarginine (hArg) and asymmetric dimethylarginine (ADMA) in patients with rheumatoid arthritis: is homoarginine a cardiovascular corrective in rheumatoid arthritis, an anti-ADMA? Int J Cardiol 176:1129–1131CrossRefPubMedGoogle Scholar
  26. Kayacelebi AA, Nguyen TH, Neil C, Horowitz JD, Jordan J, Tsikas D (2014b) Homoarginine and 3-nitrotyrosine in patients with Takotsubo cardiomyopathy. Int J Cardiol 173:546–547CrossRefPubMedGoogle Scholar
  27. Kielstein A, Tsikas D, Galloway GP, Mendelson JE (2007) Asymmetric dimethylarginine (ADMA)–a modulator of nociception in opiate tolerance and addiction? Nitric Oxide 17:55–59PubMedCentralCrossRefPubMedGoogle Scholar
  28. Kleber ME, Seppälä I, Pilz S et al (2013) Genome-wide association study identifies 3 genomic loci significantly associated with serum levels of homoarginine: the Athero Remo Consortium. Circ Cardiovasc Genet 6:505–513CrossRefPubMedGoogle Scholar
  29. Krempl TK, Maas R, Sydow K, Meinertz T, Böger RH, Kahler J (2005) Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events. Eur Heart J 26:1846–1851CrossRefPubMedGoogle Scholar
  30. Krzyzanowska K, Mittermayer F, Wolzt M, Schernthaner G (2007) Asymmetric dimethylarginine predicts cardiovascular events in patients with type 2 diabetes. Diabetes Care 30:1834–1839CrossRefPubMedGoogle Scholar
  31. Leiper JM, Santa Maria J, Chubb A et al (1999) Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 343:209–214PubMedCentralCrossRefPubMedGoogle Scholar
  32. Lenzen H, Tsikas D, Böger RH (2006) Asymmetric dimethylarginine (ADMA) and the risk for coronary heart disease: the multicenter CARDIAC Study. Eur J Clin Pharmacol 62(Suppl 1):45–49CrossRefGoogle Scholar
  33. Leong T, Zylberstein D, Graham I et al (2008) Asymmetric dimethylarginine independently predicts fatal and nonfatal myocardial infarction and stroke in women: 24-year follow-up of the population study of women in Gothenburg. Arterioscler Thromb Vasc Biol 28:961–967CrossRefPubMedGoogle Scholar
  34. Lu TM, Ding YA, Lin SJ, Lee WS, Tai HC (2003a) Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J 24:1912–1919CrossRefPubMedGoogle Scholar
  35. Lu TM, Ding YA, Charng MJ, Lin SJ (2003b) Asymmetrical dimethylarginine: a novel risk factor for coronary artery disease. Clin Cardiol 26:458–464CrossRefPubMedGoogle Scholar
  36. Maas R, Quitzau K, Schwedhelm E et al (2007) Asymmetrical dimethylarginine (ADMA) and coronary endothelial function in patients with coronary artery disease and mild hypercholesterolemia. Atherosclerosis 191:211–219CrossRefPubMedGoogle Scholar
  37. März W, Meinitzer A, Drechsler C et al (2010) Homoarginine, cardiovascular risk, and mortality. Circulation 122:967–975CrossRefPubMedGoogle Scholar
  38. Meinitzer A, Seelhorst U, Wellnitz B et al (2007) Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health Study). Clin Chem 53:273–283CrossRefPubMedGoogle Scholar
  39. Michel T (2013) R is for arginine: metabolism of arginine takes off again, in new directions. Circulation 128:1400–1404PubMedCentralCrossRefPubMedGoogle Scholar
  40. Mittermayer F, Krzyzanowska K, Exner M et al (2006) Asymmetric dimethylarginine predicts major adverse cardiovascular events in patients with advanced peripheral artery disease. Arterioscler Thromb Vasc Biol 26:2536–2540CrossRefPubMedGoogle Scholar
  41. Miyazaki H, Matsuoka H, Cooke JP et al (1999) Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 99:1141–1146CrossRefPubMedGoogle Scholar
  42. Nicholls SJ, Wang Z, Koeth R et al (2007) Metabolic profiling of arginine and nitric oxide pathways predicts hemodynamic abnormalities and mortality in patients with cardiogenic shock after acute myocardial infarction. Circulation 116:2315–2324CrossRefPubMedGoogle Scholar
  43. Perticone F, Sciacqua A, Maio R et al (2005) Asymmetric dimethylarginine, l-arginine, and endothelial dysfunction in essential hypertension. J Am Coll Cardiol 46:518–523CrossRefPubMedGoogle Scholar
  44. Pilz S, Meinitzer A, Tomaschitz A et al (2011a) Low homoarginine concentration is a novel risk factor for heart disease. Heart 97:1222–1227CrossRefPubMedGoogle Scholar
  45. Pilz S, Tomaschitz A, Meinitzer A et al (2011b) Low serum homoarginine is a novel risk factor for fatal strokes in patients undergoing coronary angiography. Stroke 42:1132–1134CrossRefPubMedGoogle Scholar
  46. Pilz S, Edelmann F, Meinitzer A et al (2014) Associations of methylarginines and homoarginine with diastolic dysfunction and cardiovascular risk factors in patients with preserved left ventricular ejection fraction. J Card Fail 20:923–930CrossRefPubMedGoogle Scholar
  47. Potena L, Fearon WF, Sydow K et al (2008) Asymmetric dimethylarginine and cardiac allograft vasculopathy progression: modulation by sirolimus. Transplantation 85:827–833CrossRefPubMedGoogle Scholar
  48. Radomski MW, Palmer RM, Moncada S (1990) An l-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci 87:5193–5197PubMedCentralCrossRefPubMedGoogle Scholar
  49. Ross R (1999) Atherosclerosis - an inflammatory disease. N Engl J Med 340:115–126CrossRefPubMedGoogle Scholar
  50. Saarelainen H, Valtonen P, Punnonen K et al (2008) Subtle changes in ADMA and l-arginine concentrations in normal pregnancies are unlikely to account for pregnancy-related increased flow-mediated dilatation. Clin Physiol Funct Imaging 28:120–124CrossRefPubMedGoogle Scholar
  51. Schnabel R, Blankenberg S, Lubos E et al (2005) Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res 97:e53–e59CrossRefPubMedGoogle Scholar
  52. Schulze F, Lenzen H, Hanefeld C et al (2006) Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) study. Am Heart J 152:493.e1–493.e8CrossRefGoogle Scholar
  53. Schwedhelm E, Wallaschofski H, Atzler D, et al. (2014) Incidence of all-cause and cardiovascular mortality predicted by symmetric dimethylarginine in the population-based study of health in Pomerania. PLoS One 9(5):e96875Google Scholar
  54. Selcuk MT, Selcuk H, Temizhan A et al (2007) Asymmetric dimethylarginine plasma concentrations and l-arginine/asymmetric dimethylarginine ratio in patients with slow coronary flow. Coron Artery Dis 18:545–551CrossRefPubMedGoogle Scholar
  55. Sobczak A, Prokopowicz A, Radek M et al (2014) Tobacco smoking decreases plasma concentration of the emerging cardiovascular risk marker, l-homoarginine. Circ J 78:1254–1258CrossRefPubMedGoogle Scholar
  56. Tousoulis D, Koutsogiannis M, Papageorgiou N et al (2010) Endothelial dysfunction: potential clinical implications. Minerva Med 101:271–284PubMedGoogle Scholar
  57. Tousoulis D, Bouras G, Antoniades C et al (2011a) Methionine-induced homocysteinemia impairs endothelial function in hypertensives: the role of asymmetrical dimethylarginine and antioxidant vitamins. Am J Hypertens 24:936–942CrossRefPubMedGoogle Scholar
  58. Tousoulis D, Kampoli AM, Papageorgiou N et al (2011b) Pathophysiology of atherosclerosis: the role of inflammation. Curr Pharm Des 17:4089–4110CrossRefPubMedGoogle Scholar
  59. Tousoulis D, Psaltopoulou T, Androulakis E et al (2015) Oxidative stress and early atherosclerosis: novel antioxidant treatment. Cardiovasc Drugs Ther 29:75–88CrossRefPubMedGoogle Scholar
  60. Tran CT, Leiper JM, Vallance P (2003) The DDAH/ADMA/NOS pathway. Atheroscler Suppl 4:33–40CrossRefPubMedGoogle Scholar
  61. Tsikas D, Kayacelebi AA (2014) Do homoarginine and asymmetric dimethylarginine act antagonistically in the cardiovascular system? Circ J 78:2094–2095CrossRefPubMedGoogle Scholar
  62. Tsikas D, Böger RH, Sandmann J, Bode-Böger SM, Frölich JC (2000a) Endogenous nitric oxide synthase inhibitors are responsible for the l-arginine paradox. FEBS Lett 478:1–3CrossRefPubMedGoogle Scholar
  63. Tsikas D, Sandmann J, Savva A et al (2000b) Assessment of nitric oxide synthase activity in vitro and in vivo by gas chromatography-mass spectrometry. J Chromatogr 742:143–153CrossRefGoogle Scholar
  64. Valkonen VP, Paiva H, Salonen JT et al (2001) Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 358:2127–2128CrossRefPubMedGoogle Scholar
  65. 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 339:572–575CrossRefPubMedGoogle Scholar
  66. Valtonen P, Laitinen T, Lyyra-Laitinen T et al (2008) Serum l-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation. Circ J 72:1879–1884CrossRefPubMedGoogle Scholar
  67. van der Zwan LP, Davids M, Scheffer PG, Dekker JM, Stehouwer CD, Teerlink T (2013) l-Homoarginine and l-arginine are antagonistically related to blood pressure in an elderly population: the Hoorn Study. J Hypertens 31:1114–1123CrossRefPubMedGoogle Scholar
  68. Vogl L, Pohlhammer J, Meinitzer A et al (2015) Serum concentrations of l-arginine and l-homoarginine in male patients with intermittent claudication: a cross-sectional and prospective investigation in the CAVASIC Study. Atherosclerosis 239:607–614CrossRefPubMedGoogle Scholar
  69. Zoccali C, Bode-Böger S, Mallamaci F et al (2001) Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358:2113–2117CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Nikolaos Papageorgiou
    • 1
  • Emmanuel Androulakis
    • 1
  • Spyridon Papaioannou
    • 1
  • Charalambos Antoniades
    • 1
  • Dimitris Tousoulis
    • 1
    Email author
  1. 1.1st Cardiology DepartmentAthens University Medical SchoolAthensGreece

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