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Horm Metab Res 2011; 43(5): 343-348
DOI: 10.1055/s-0031-1271778
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Weight Loss Improves Endothelial Function Independently of ADMA Reduction in Severe Obesity

G. Rudofsky1 , E. Roeder1 , 2 , T. Merle1 , M. Hildebrand1 , P. P. Nawroth1 , C. Wolfrum2
  • 1Department of Endocrinology and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
  • 2Swiss Federal Institute of Technology, Institute of Food Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland
Further Information

Publication History

received 22.11.2010

accepted 27.01.2011

Publication Date:
01 March 2011 (online)

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Abstract

This prospective study was performed in order to establish whether improvement of endothelial function after weight reduction can be explained by a decrease of elevated asymmetric dimethyl arginine (ADMA), an inhibitor of endogenous NO-synthase (eNOS). Therefore, 21 obese subjects (BMI: 41.1±6.4 kg/m2) were studied at baseline and after 12 weeks of weight reduction with a very low calorie diet. Biochemical and clinical parameters of endothelial function were assessed before and after weight loss. Biochemical parameters were determined by measurement of ADMA and soluble intercellular adhesion molecule (sICAM). Clinical parameters were assessed by pulse wave analysis (PWA). Weight intervention resulted in a 21.4±6.8 kg reduction of body weight from 119.7±12.8 kg at study start to 98.3±11.6 kg at study end (p<0.001). Accordingly, biochemical markers improved under weight reduction (ADMA from 0.47±0.07 mmol/l to 0.42±0.08 mmol/l; p=0.002; ICAM from 276±42 ng/ml to 236±29 ng/ml; p<0.001). Further, clinical parameters of functional endothelial function improved with an increase of deltaRI after salbutamol inhalation from −1% before to −9% after weight reduction (p=0.02). Interestingly, improvement of endothelial function correlated with improved HOMA index only (r=−0.60, p=0.04) but not with reduced ADMA levels, improved hypertension or reduced body weight. In conclusion, weight reduction with a very low calorie diet improves endothelial function measured by pulse wave velocity. The missing correlation with ADMA suggests possible further mechanisms underlying this observed effect, for example, improvement of insulin resistance.

Key words

weight loss - pulse wave analysis - ADMA - sICAM - obesity - endothelial dysfunction

References

  • 1 Ross R. Atherosclerosis – an inflammatory disease.  N Engl J Med. 1998;  334 1349-1357
    Google Scholar
  • 2 Bray GA, Clearfield MB, Fintel DJ, Nelinson DS. Overweight and obesity: the pathogenesis of cardiometabolic risk.  Clinical Cornerstone. 2009;  9 30-42
    Google Scholar
  • 3 Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP. Endothelial dysfunction in metabolic syndrome: Prevalence, pathogenesis and management.  Nutr Metab Cardiovasc Dis. 2010;  20 140-146
    Google Scholar
  • 4 Hashimoto M, Akishita M, Eto M, Kozaki K, Ako J, Sugimoto N, Yoshizumi M, Toba K, Ouchi Y. The impairment of flow-mediated vasodilatation in obese men with visceral fat accumulation.  Int J Obes. 1998;  22 477-484
    Google Scholar
  • 5 Arkin JM, Alsdorf R, Bigornia S, Palmisano J, Beal R, Istfan N, Hess D, Apovian CM, Gokce N. Relation of cumulative weight burden to vascular endothelial dysfunction in obesity.  Am J Cardiol. 2008;  101 98-101
    Google Scholar
  • 6 Fuchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.  Nature. 1980;  288 373-376
    Google Scholar
  • 7 Rudofsky Jr G, Reismann P, Grafe IA, Konrade I, Djuric Z, Tafel J, Buchbinder S, Zorn M, Humpert PM, Hamann A, Morcos M, Nawroth PP, Bierhaus A. Improved vascular function upon pioglitazone treatment in type 2 diabetes is not associated with changes in mononuclear NF-kappaB binding activity.  Horm Metab Res. 2007;  39 665-671
    Google Scholar
  • 8 Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.  J Clin Invest. 1996;  97 2601-2610
    Google Scholar
  • 9 Hamdy O, Ledbury S, Mullooly C, Jarema C, Porter S, Ovalle K, Moussa A, Caselli A, Caballero AE, Economides PA, Veves A, Horton ES. Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome.  Diabetes Care. 2003;  26 2119-2125
    Google Scholar
  • 10 Sciacqua A, Candigliota M, Ceravolo R, Scozzafava A, Sinopoli F, Corsonello A, Sesti G, Perticone F. Weight loss in combination with physical activity improves endothelial dysfunction in human obesity.  Diabetes Care. 2003;  26 1673-1678
    Google Scholar
  • 11 Brook RD. Obesity, weight loss, and vascular function.  Endocrine. 2006;  29 21-25
    Google Scholar
  • 12 McLaughlin T, Stühlinger M, Lamendola C, Abbasi F, Bialek J, Reaven GM, Tsao PS. Plasma asymmetric dimethylarginine concentrations are elevated in obese insulin-resistant women and fall with weight loss.  J Clin Endocrinol Metab. 2006;  91 1896-1900
    Google Scholar
  • 13 Leiper J, Vallance P. Biological significance of endogenous methylarginines that inhibit nitric oxide synthases.  Cardiovasc Res. 1999;  43 542-548
    Google Scholar
  • 14 Marliss EB, Chevalier S, Gougeon R, Morais JA, Lamarche M, Adegoke OA, Wu G. Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover.  Diabetologia. 2006;  49 351-359
    Google Scholar
  • 15 Boeger RH. Asymmetric dimethylarginine (ADMA): A novel risk marker in cardiovascular medicine and beyond.  Ann Med. 2006;  38 126-136
    Google Scholar
  • 16 Closs EI, Basha FZ, 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
    Google Scholar
  • 17 Azuma H, Sato J, Hamasaki H, Sugimoto A, Isotani E, Obayashi S. Accumulation of endogenous inhibitors for nitric oxide synthesis and decreased content of L-arginine in regenerated endothelial cells.  Br J Pharmacol. 1995;  115 1001-1004
    Google Scholar
  • 18 Jang JJ, Ho HK, Kwan HH, Fajardo LF, Cooke JP. Angiogenesis is impaired by hypercholesterolemia: role of asymmetric dimethylarginine.  Circulation. 2000;  102 1414-1419
    Google Scholar
  • 19 Boeger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Boeger SM. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases.  Circ Res. 2000;  87 99-105
    Google Scholar
  • 20 Schnabel R, Blankenberg S, Lubos E, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Jachmann N, Post F, Peetz D, Bickel C, Cambien F, Tiret L, Muenzel T. Asymmetric Dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease.  Circ Res. 2005;  97 e53-e59
    Google Scholar
  • 21 Boeger RH, Bode-Boeger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia.  Circulation. 1998;  98 1842-1847
    Google Scholar
  • 22 Surdacki A, Nowicki M, Sandmann J, Tsikas D, Boeger RH, Bode-Boeger SM, Kruszelnicka-Kwiatkowska O, Kokot F, Dubiel JS, Froelich JC. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension.  J Cardiovasc Pharmacol. 1999;  33 652-658
    Google Scholar
  • 23 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
    Google Scholar
  • 24 Konukoglu D, Uzun H, Firtina S, Cigdem Arica P, Kocael A, Taskin M. Plasma adhesion and inflammation markers: asymmetrical dimethyl-L-arginine and secretory phospholipase A2 concentrations before and after laparoscopic gastric banding in morbidly obese patients.  Obes Surg. 2007;  17 672-678
    Google Scholar
  • 25 Wilkinson IB, Hall IR, MacCallum H, Mackenzie IS, McEniery CM, van der Arend BJ, Shu YE, MacKay LS, Webb DJ, Cockcroft JR. Pulse-wave analysis: clinical evaluation of a noninvasive, widely applicable method for assessing endothelial function.  Arterioscler Thromb Vasc Biol. 2002;  22 147-152
    Google Scholar
  • 26 Sourij H, Zweiker R, Wascher TC. Effects of pioglitazone on endothelial function, insulin sensitivity, and glucose control in subjects with coronary artery disease and new-onset type 2 diabetes.  Diab Care. 2006;  29 1039-1045
    Google Scholar
  • 27 Woodman RJ, Watts GF. Measurement and application of arterial stiffness in clinical research: focus on new methodologies and diabetes mellitus.  Med Sci Monit. 2003;  9 RA81-RA89
    Google Scholar
  • 28 Thum T, Tsikas D, Stein S, Schultheiss M, Eigenthaler M, Anker SD, Poole-Wilson PA, Ertl G, Bauersachs J. Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous inhibitor asymmetric dimethylarginine.  J Am Coll Cardiol. 2005;  46 1693-1701
    Google Scholar
  • 29 Anderssohn M, Schwedhelm E, Lüneburg N, Vasan RS, Böger RH. Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus.  Diab Vasc Dis Res. 2010;  7 105-118
    Google Scholar
  • 30 Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms.  Circulation. 2006;  113 1888-1904
    Google Scholar
  • 31 Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle.  J Clin Invest. 2000;  105 311-320
    Google Scholar
  • 32 Madonna R, Pandolfi A, Massaro M, Consoli A, De Caterina R. Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase.  Diabetologia. 2004;  47 532-536
    Google Scholar
  • 33 Suzuki M, Takamisawa I, Yoshimasa Y, Harano Y. Association between insulin resistance and endothelial dysfunction in type 2 diabetes and the effects of pioglitazone.  Diabetes Res Clin Pract. 2007;  76 12-17
    Google Scholar
  • 34 Marx N, Duez H, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells.  Circ Res. 2004;  94 1168-1178
    Google Scholar
  • 35 Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.  Circulation. 1993;  88 2149-2155
    Google Scholar

Correspondence

G. RudofskyMD 

Department of Medicine I and

Clinical Chemistry

Im Neuenheimer Feld 410

69120 Heidelberg

Germany

Phone: +49/6221/563 86 20

Fax: +49/6221/565 793

Email: gottfried_rudofsky@med.uni-heidelberg.de