Skip to main content
SpringerLink
Log in

Increased asymmetric dimethylarginine (ADMA) dimethylaminohydrolase (DDAH) activity in childhood hypercholesterolemia type II

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Asymmetric dimethylarginine (ADMA) systemic concentrations are elevated in hypercholesterolemic adults and contribute to nitric oxide (NO) dependent endothelial dysfunction. Decreased activity of the key ADMA-hydrolyzing enzyme dimethylarginine dimethylaminohydrolase (DDAH) may be involved. Yet, the ADMA/DDAH/NO pathway has not been investigated in childhood hypercholesterolemia. We studied 64 children with hypercholesterolemia type II (HCh-II) and 54 normocholesterolemic (NCh) children (mean ± SD; age, years: 11.1 ± 3.5 vs. 11.9 ± 4.6). Plasma and urine ADMA was measured by GC–MS/MS. Dimethylamine (DMA), the ADMA metabolite, creatinine, nitrite and nitrate in urine were measured by GC–MS. The DMA/ADMA molar ratio in urine was calculated to estimate whole body DDAH activity. ADMA plasma concentration (mean ± SD; nM: 571 ± 85 vs. 542 ± 110, P = 0.17) and ADMA urinary excretion rate (mean ± SD: 7.1 ± 2 versus 7.2 ± 3 μmol/mmol creatinine, P = 0.6) were similar in HCh-II and NCh children. Both DMA excretion rate [median (25th–75th percentile): 56.3 (46.4–109.1) vs. 45.2 (22.2–65.5) μmol/mmol creatinine, P = 0.0004] and DMA/ADMA molar ratio [median (25th–75th percentile): 9.2 (6.0–16.3) vs. 5.4 (3.8–9.4), P = 0.0004] were slightly but statistically significantly increased in HCh-II children compared to NCh children. Plasma and urinary nitrite and nitrate were similar in both groups. In HCh-II whole body DDAH activity is elevated as compared to NCh. HCh-II children treated with drugs for hypercholesterolemia had lower plasma ADMA levels than untreated HCh-II or NCh children, presumably via increased DDAH activity. Differences between treated and untreated HCh-II children were not due to differences in age. In conclusion, HCh-II children do not have elevated ADMA plasma levels, largely due to an apparent increase in DDAH activity. While this would tend to limit development of endothelial dysfunction, it is not clear whether this might be medication-induced or represent a primary change in HCh-II children.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Becker T, Mevius I, de Vries DK, Schaaherder AFM, Meyer zu Vilsendorf A, Klempnauer J, Frölich JC, Tsikas D (2009) The l-arginine/NO pathway in end-stage liver disease and during orthotopic liver and kidney transplantation: biological and analytical ramifications. Nitric Oxide 20:61–67

    Article  PubMed  CAS  Google Scholar 

  • Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP (1998) Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 98:1842–1847

    Article  PubMed  Google Scholar 

  • Böger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Böger SM (2000) LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 87:99–105

    Article  PubMed  Google Scholar 

  • Brooks ER, Langman CB, Wang S, Price HE, Hodges AL, Darling L, Yang AZ, Smith FA (2009) Methylated arginine derivatives in children and adolescents with chronic kidney disease. Pediatr Nephrol 24:129–134

    Article  PubMed  Google Scholar 

  • Eid HM, Eritsland J, Larsen J, Arnesen H, Seljeflot I (2003) Increased levels of asymmetric dimethylarginine in populations at risk for atherosclerotic disease. Effects of pravastatin. Atherosclerosis 166:279–284

    Article  PubMed  CAS  Google Scholar 

  • Gladwin MT, Schechter AN, Kim-Shapiro DB, Patel RP, Hogg N, Shiva S, Cannon RO 3rd, Kelm M, Wink DA, Espey MG, Oldfield EH, Pluta RM, Freeman BA, Lancaster JR Jr, Feelisch M, Lundberg JO (2005) The emerging biology of the nitrite anion. Nat Chem Biol 1:308–314

    Article  PubMed  CAS  Google Scholar 

  • Goonasekera CDA, Rees DD, Woolard P, Frend A, Shah V, Dillon MJ (1997) Nitric oxide synthase inhibitors and hypertension in children and adolescents. J Hypertens 15:901–909

    Article  PubMed  CAS  Google Scholar 

  • Horowitz JD, Heresztyn T (2007) An overview of plasma concentrations of asymmetric dimethylarginine (ADMA) in health and disease and in clinical studies. J Chromatogr B 851:42–50

    Article  CAS  Google Scholar 

  • Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP (1999) Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 99:3092–3095

    Article  PubMed  CAS  Google Scholar 

  • Jehlicka P, Stozicky F, Mayer OJR, Varvarovska J, Racek J, Trefil L, Siala K (2009) Asymmetric dimethylarginine an the effect of folat substitution in children with familial hypercholesterolemia and diabetes mellitus type 1. Physiol Res 58:179–184

    PubMed  CAS  Google Scholar 

  • Kanzelmeyer N, Tsikas D, Chobanyan-Jürgens K, Beckmann B, Vaske B, Illsinger S, Das AM, Lücke T (2011) Asymmetric dimethylarginine in children with homocystinuria or phenylketonuria. Amino Acids. doi:10.1007/s00726-011-0892

  • Leiper JM, Vallance P (2006) The synthesis and metabolism of asymmetric dimethylarginine (ADMA). Eur J Clin Pharmacol 62:33–38

    Article  Google Scholar 

  • Lu TM, Ding YA, Leu HB, Yin WH, Sheu WH, Chu KM (2004) Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am J Cardiol 94:157–161

    Article  PubMed  CAS  Google Scholar 

  • Lücke T, Tsikas D, Kanzelmeyer N, Vaske B, Das AM (2006) Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine in citrullinemia. Metabolism 55:1599–1603

    Article  PubMed  Google Scholar 

  • Lücke T, Kanzelmeyer N, Kemper MJ, Tsikas D, Das AM (2007) Developmental changes in the l-arginine/nitric oxide pathway from infancy to adulthood: plasma asymmetric dimethylarginine levels decrease with age. Clin Chem Lab Med 45:1525–1530

    Article  PubMed  Google Scholar 

  • Lücke T, Kanzelmeyer N, Chobanyan K, Tsikas D, Franke D, Kemper MJ, Ehrich JH, Das AM (2008) Elevated asymmetric dimethylarginine (ADMA) and inverse correlation between circulating ADMA and glomerular filtration rate in children with sporadic focal segmental glomerulosclerosis (FSGS). Nephrol Dial Transplant 23:734–740

    Article  PubMed  Google Scholar 

  • Nakamura T, Sato E, Fujiwara N, Kawagoe Y, Ueda Y, Suzuki T, Ueda S, Adachi H, Okuda S, Yamagishi S (2009) Ezetimibe decreases serum levels of asymmetric dimethylarginine (ADMA) and ameliorates renal injury in non-diabetic chronic kidney disease patients in a cholesterol-independent manner. Pharmacol Res 60:525–528

    Article  PubMed  CAS  Google Scholar 

  • Nanayakkara PW, Kiefte-de Jong JC, ter Wee PM, Stehouwer CD, van Ittersum FJ, Olthof MR, Teerlink T, Twisk JW, van Guldener C, Smulders YM (2009) Randomized placebo-controlled trial assessing a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on plasma asymmetric dimethylarginine concentration in mild to moderate CKD. Am J Kidney Dis 53:41–50

    Article  PubMed  CAS  Google Scholar 

  • Oguz A, Uzunlulu M (2008) Short term fluvastatin treatment lowers serum asymmetric dimethylarginine levels in patients with metabolic syndrome. Int Heart J 49:303–311

    Article  PubMed  CAS  Google Scholar 

  • Palm M, Onozato ML, Luo Z, Wilcox CS (2007) Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293:3227–3245

    Article  Google Scholar 

  • Surdacki A, Tsikas D, Mayatepek E, Frölich JC (2003) Elevated urinary excretion of nitric oxide metabolites in young infants with Zellweger syndrome. Clin Chim Acta 334:111–115

    Article  PubMed  CAS  Google Scholar 

  • Tan B, Jiang DJ, Huang H, Jia SJ, Jiang JL, Hu CP, Li YJ (2007) Taurine protects against low-density lipoprotein-induced endothelial dysfunction by the DDAH/ADMA pathway. Vascul Pharmacol 46:338–345

    Article  PubMed  CAS  Google Scholar 

  • Tsikas D (2000) Simultaneous derivatization and quantification of the nitric oxide metabolites nitrite and nitrate in biological fluids by gas-chromatography/mass spectrometry. Anal Chem 72:4064–4072

    Article  PubMed  CAS  Google Scholar 

  • Tsikas D (2008a) A critical review and discussion of analytical methods in the l-arginine/nitric oxide (NO) area of basic and clinical research. Anal Biochem 379:139–163

    Article  PubMed  CAS  Google Scholar 

  • Tsikas D (2008b) Determination of asymmetric dimethylarginine (ADMA) in biological fluids: a paradigm for a successful analytical story. Curr Opin Clin Nutr Metab Care 11:592–600

    Article  PubMed  CAS  Google Scholar 

  • Tsikas D, Schubert B, Gutzki FM, Sandmann J, Frölich JC (2003) Quantitative determination of circulating and urinary asymmetric dimethylarginine (ADMA) in humans by gas chromatographytandem mass spectrometry as methyl ester tri (N-pentafluoropropionyl) derivative. J Chromatogr B 798:87–99

    Google Scholar 

  • Tsikas D, Thum T, Becker T, Pham VV, Chobanyan K, Mitschke A, Beckmann B, Gutzki FM, Bauersachs J, Stichtenoth DO (2007) Accurate quantification of dimethylamine (DMA) in human urine by gas chromatography-mass spectrometry as pentafluorobenzamide derivative: evaluation of the relationship between DMA and its precursor asymmetric dimethylarginine (ADMA) in health and disease. J Chromatogr B 851:229–239

    Article  CAS  Google Scholar 

  • Tsikas D, Schwarz A, Stichtenoth DO (2010) Simultaneous measurement of [15N]nitrate and [15N]nitrite enrichment and concentration in urine by gas chromatography mass spectrometry as pentafluorobenzyl derivatives. Anal Chem 82:2585–2587

    Article  PubMed  CAS  Google Scholar 

  • Wolf C, Lorenzen JM, Stein S, Tsikas D, Störk S, Weidemann F, Ertl G, Anker S, Bauersachs J, Thum T (2011) Urinary asymmetric dimethylarginine (ADMA) is a predictor of mortality risk in patients with coronary artery disease. Int J Cardiol. doi:10.1016/j.ijcard.2010.11.003

  • Wu G (2009) Amino acids: metabolism, functions, and nutrition. Amino Acids 37:1–17

    Article  PubMed  Google Scholar 

  • Wu G, Bazer FW, Davis TA, Kim SW, Li P, Rhoads JM, Satterfield MC, Smith SB, Spencer TE, Yin YL (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank B. Beckmann and A. Mitschke for excellent laboratory assistance and F.-M. Gutzki for performing GC–MS and GC–MS/MS analyses. We are also thankful to Deutsches Stiftungszentrum (die Stiftung Dr. Edith Grünheit; S150/10028/2010) for the travel support given to KCJ for the presentation of the study results at the 5th International Symposium on ADMA, Chicago/Ill, 2010.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Paediatrics, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany

    Kristine Chobanyan-Jürgens, Nele Kanzelmeyer, Anibh M. Das & Sabine Illsinger

  2. Department of Paediatrics, University of Mayence, Mayence, Germany

    Anne-Jule Fuchs

  3. Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany

    Dimitrios Tsikas & Jens Jordan

  4. Institute of Biometry, Hannover Medical School, Hannover, Germany

    Bernhard Vaske

  5. Department of Neuropaediatrics, Children’s Hospital, University of Bochum, Bochum, Germany

    Thomas Lücke

Authors
  1. Kristine Chobanyan-Jürgens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne-Jule Fuchs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dimitrios Tsikas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nele Kanzelmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anibh M. Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sabine Illsinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernhard Vaske
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jens Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas Lücke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kristine Chobanyan-Jürgens.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chobanyan-Jürgens, K., Fuchs, AJ., Tsikas, D. et al. Increased asymmetric dimethylarginine (ADMA) dimethylaminohydrolase (DDAH) activity in childhood hypercholesterolemia type II. Amino Acids 43, 805–811 (2012). https://doi.org/10.1007/s00726-011-1136-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-011-1136-3

Keywords

Search

Navigation