RSS-Feed abonnieren
DOI: 10.1055/s-0031-1271778
© Georg Thieme Verlag KG Stuttgart · New York
Weight Loss Improves Endothelial Function Independently of ADMA Reduction in Severe Obesity
Publikationsverlauf
received 22.11.2010
accepted 27.01.2011
Publikationsdatum:
01. März 2011 (online)
![](https://www.thieme-connect.de/media/hmr/201105/lookinside/thumbnails/10.1055-s-0031-1271778-1.jpg)
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
- 2 Bray GA, Clearfield MB, Fintel DJ, Nelinson DS. Overweight and obesity: the pathogenesis of cardiometabolic risk. Clinical Cornerstone. 2009; 9 30-42
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 11 Brook RD. Obesity, weight loss, and vascular function. Endocrine. 2006; 29 21-25
- 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
- 13 Leiper J, Vallance P. Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res. 1999; 43 542-548
- 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
- 15 Boeger RH. Asymmetric dimethylarginine (ADMA): A novel risk marker in cardiovascular medicine and beyond. Ann Med. 2006; 38 126-136
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Correspondence
G. RudofskyMD
Department of Medicine I and
Clinical Chemistry
Im Neuenheimer Feld 410
69120 Heidelberg
Germany
Telefon: +49/6221/563 86 20
Fax: +49/6221/565 793
eMail: gottfried_rudofsky@med.uni-heidelberg.de