Asymmetric Dimethylarginine (ADMA) is Tightly Correlated with Growth in Juveniles without Correlations to Obesity Related Disorders

Abstract

Background: Asymmetrical dimethylarginine (ADMA) was found to be increased in conditions associated with atherosclerosis and metabolic disorders. We investigated ADMA in obese juveniles with pre-atherosclerotic symptoms and in normal weight juveniles.

Design: To elucidate correlations of ADMA in juveniles with obesity related disorders such as insulin resistance, low grade inflammation, hypertension and pre-atherosclerosis, we analysed ADMA by high performance liquid chromatography (HPLC) in 68 obese and 68 healthy, age and gender matched juveniles.

Results: ADMA levels are slightly, but significantly increased (p=0.04) in obese (0.78±0.01 μmol/l), compared to normal weight juveniles (0.74±0.01 μmol/l). There are no robust correlations of ADMA with obesity related disorders, like dyslipidemia, hypertension, low-grade inflammation and pre-atherosclerosis. Age, body length and alkaline phosphatase, as markers of growth are correlated with ADMA. Multiple testing revealed that, alkaline phosphatase turned out as highly significant positively correlated with ADMA in normal weight (r=0.45/p<0.0001) and obese (r=0.59/p<0.0001) children.

Conclusions: We show here, that ADMA is slightly increased in obese juveniles without any robust correlations to obesity related disorders. ADMA is tightly correlated with alkaline phosphatase as a marker of growth in obese and normal weight, healthy juveniles.

References

• 1 Szuba A, Podgorski M. Asymmetric dimethylarginine (ADMA) a novel cardiovascular risk factor - evidence from epidemiological and prospective clinical trials.  Pharmacol Rep. 2006;  58 ((Suppl)) 16-20
• 2 Blackwell S, O’Reilly DS, Talwar D. Biological variation of asymmetric dimethylarginine and related arginine metabolites and analytical performance goals for their measurement in human plasma.  Eur J Clin Invest. 2007;  37 364-371
• 3 Boger RH, Vallance P, Cooke JP. Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase.  Atheroscler Suppl. 2003;  4 1-3
• 4 Boger RH. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor.  Cardiovasc Res. 2003;  59 824-833
• 5 Cooke JP. Asymmetrical dimethylarginine: the Uber marker?.  Circulation. 2004;  109 1813-1818
• 6 Lundman P, Eriksson MJ, Stuhlinger 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
• 7 Zoccali C, Bode-Boger S, Mallamaci F. et al . Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.  Lancet. 2001;  358 2113-2117
• 8 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
• 9 Stuhlinger MC, Stanger O. Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction.  Curr Drug Metab. 2005;  6 3-14
• 10 Stuhlinger MC, Abbasi F, Chu JW. et al . Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor.  Jama. 2002;  287 1420-1426
• 11 Ravani P, Tripepi G, Malberti F. et al . Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach.  J Am Soc Nephrol. 2005;  16 2449-2455
• 12 Siroen MP, Leeuwen PA van, Nijveldt RJ. et al . Modulation of asymmetric dimethylarginine in critically ill patients receiving intensive insulin treatment: a possible explanation of reduced morbidity and mortality?.  Crit Care Med. 2005;  33 504-510
• 13 Schnabel R, Blankenberg S, Lubos E. 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 e53-59
• 14 Meinitzer A, Seelhorst U, Wellnitz B. et al . Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health study).  Clin Chem. 2007;  53 273-283
• 15 Goonasekera CD, Rees DD, Woolard P. et al . Nitric oxide synthase inhibitors and hypertension in children and adolescents.  J Hypertens. 1997;  15 901-909
• 16 Goonasekera CD, Shah V, Rees DD, Dillon MJ. Nitric oxide activity in childhood hypertension.  Arch Dis Child. 1997;  77 11-16
• 17 Mangge H, Schauenstein K, Stroedter L. et al . Low grade inflammation in juvenile obesity and type 1 diabetes associated with early signs of atherosclerosis.  Exp Clin Endocrinol Diabetes. 2004;  112 378-382
• 18 Kiechl S, Willeit J. The natural course of atherosclerosis. Part II: vascular remodelling. Bruneck Study Group.  Arterioscler Thromb Vasc Biol. 1999;  19 1491-1498
• 19 Winkelmann BR, Marz W, Boehm BO. et al . Rationale and design of the LURIC study–a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease.  Pharmacogenomics. 2001;  2 1-73
• 20 Achan V, Broadhead M, Malaki M. et al . Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase.  Arterioscler Thromb Vasc Biol. 2003;  23 1455-1459
• 21 Curgunlu A, Uzun H, Bavunoglu I. et al . Increased circulating concentrations of asymmetric dimethylarginine (ADMA) in white coat hypertension.  J Hum Hypertens. 2005;  19 629-633
• 22 Miyazaki H, Matsuoka H, Cooke JP. et al . Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis.  Circulation. 1999;  99 1141-1146
• 23 Cetinalp-Demircan P, Can A, Bekpinar S, Unlucerci Y, Orhan Y. Unchanged asymmetric dimethylarginine levels in non-diabetic, premenopausal obese women who have common risk factors for cardiovascular disease.  Endocrine. 2007;  31 100-104
• 24 Krzyzanowska K, Mittermayer F, Kopp HP, Wolzt M, Schernthaner G. Weight loss reduces circulating asymmetrical dimethylarginine concentrations in morbidly obese women.  J Clin Endocrinol Metab. 2004;  89 6277-6281
• 25 Boger RH. Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials.  Vasc Med. 2005;  10 ((Suppl 1)) 19-25
• 26 Boger RH, Bode-Boger SM, Szuba A. et al . Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia.  Circulation. 1998;  98 1842-1847
• 27 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
• 28 Paiva H, Laakso J, Lehtimaki T. et al . Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors.  J Cardiovasc Pharmacol. 2003;  41 219-222
• 29 Kocak H, Gumuslu S, Ermis C. et al . Oxidative Stress and Asymmetric Dimethylarginine Is Independently Associated with Carotid Intima Media Thickness in Peritoneal Dialysis Patients.  Am J Nephrol. 2007;  28 91-96
• 30 Lucke T, Kanzelmeyer N, Kemper MJ, Tsikas D, Das AM. Developmental changes in the L-arginine/nitric oxide pathway from infancy to adulthood: plasma asymmetric dimethylarginine levels decrease with age.  Clin Chem Lab Med. 2007;  45 1525-1530
• 31 Schulze F, Maas R, Freese R. et al . Determination of a reference value for N(G), N(G)-dimethyl-L-arginine in 500 subjects.  Eur J Clin Invest. 2005;  35 622-626
• 32 Holden DP, Cartwright JE, Nussey SS, Whitley GS. Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine.  Circulation. 2003;  108 1575-1580
• 33 Hulley S, Grady D, Bush T. et al . Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.  Jama. 1998;  280 605-613
• 34 Post MS, Verhoeven MO, Mooren MJ van der. et al . Effect of hormone replacement therapy on plasma levels of the cardiovascular risk factor asymmetric dimethylarginine: a randomized, placebo-controlled 12-week study in healthy early postmenopausal women.  J Clin Endocrinol Metab. 2003;  88 4221-4226
• 35 Rossouw JE, Anderson GL, Prentice RL. et al . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.  Jama. 2002;  288 321-333
• 36 Schildkraut JM, Cooper GS, Halabi S. et al . Age at natural menopause and the risk of epithelial ovarian cancer.  Obstet Gynecol. 2001;  98 85-90
• 37 Teerlink T, Neele SJ, Jong S de, Netelenbos JC, Stehouwer CD. Oestrogen replacement therapy lowers plasma levels of asymmetrical dimethylarginine in healthy postmenopausal women.  Clin Sci (Lond). 2003;  105 67-71

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