CLINICAL RESEARCH: CHRONIC CORONARY ARTERY DISEASE
Suppression of Endothelial Progenitor Cells in Human Coronary Artery Disease by the Endogenous Nitric Oxide Synthase Inhibitor Asymmetric Dimethylarginine
Thomas Thum, MD*, ,*,
Dimitrios Tsikas, PhD ,
Sylvia Stein*,
Maximilian Schultheiss*,
Martin Eigenthaler, MD ,
Stefan D. Anker, MD, PhD,
Philip A. Poole-Wilson, MD, FRCP,
Georg Ertl, MD* and
Johann Bauersachs, MD*
* Bayerische Julius-Maximilians-Universität, Medizinische Klinik I, Würzburg, Germany
Medizinische Hochschule, Institut für Klinische Pharmakologie, Hannover, Germany
Bayerische Julius-Maximilians-Universität, Institut für Klinische Biochemie und Pathobiochemie, Universität Würzburg, Würzburg, Germany
Imperial College London, National Heart and Lung Institute and Faculty of Medicine, London, United Kingdom
Manuscript received February 22, 2005;
revised manuscript received April 8, 2005,
accepted April 27, 2005.
* Reprint requests and correspondence: Dr. Thomas Thum, Medizinische Universitätsklinik, Josef-Schneider-Strasse 2, D-97080, Würzburg, Germany (Email: thum_t{at}medizin.uni-wuerzburg.de).
OBJECTIVES: We tested the hypothesis that asymmetric dimethylarginine (ADMA) may be an endogenous inhibitor of endothelial progenitor cells (EPCs).
BACKGROUND: Endothelial progenitor cells play a pivotal role in regeneration of injured endothelium, thereby limiting the formation of atherosclerotic lesions. Reduced numbers of EPCs may affect progression of coronary artery disease. Regulation of EPC mobilization and function is mediated in part by nitric oxide (NO). Endogenous inhibitors of NO synthases, such as ADMA, contribute to endothelial dysfunction and injury.
METHODS: We used flow cytometry and in vitro assays to investigate the relationship between EPC number and function with ADMA plasma levels in patients with stable angina.
RESULTS: The plasma concentration of ADMA was related to the severity of coronary artery disease and correlated inversely with the number of circulating CD34+/CD133+ progenitor cells (r = –0.69; p < 0.0001) and endothelial colony forming units (CFUs) (r = –0.75; p < 0.0001). Adjusting for all patient characteristics, we confirmed these findings in multivariate regression analyses. In vitro differentiation of EPCs was repressed by ADMA in a concentration-dependent manner. Compared with untreated cells, ADMA reduced EPC incorporation into endothelial tube-like structures to 27 ± 11% (p < 0.001). Asymmetric dimethylarginine repressed the formation of CFUs from cultured peripheral blood mononuclear cells to 35 ± 7% (p < 0.001). Asymmetric dimethylarginine decreased endothelial nitric oxide synthase activity in EPCs to 64 ± 6% (p < 0.05) when compared with controls. Co-incubation with the hydroxymethyl glutaryl coenzyme A reductase inhibitor rosuvastatin abolished the detrimental effects of ADMA.
CONCLUSIONS: Asymmetric dimethylarginine is an endogenous inhibitor of mobilization, differentiation, and function of EPCs. This contributes to the cardiovascular risk in patients with high ADMA levels and may explain low numbers and function of EPCs in patients with coronary artery disease.
|
Abbreviations and Acronyms
| | ADMA = asymmetric dimethylarginine | | CAD = coronary artery disease | | CFU = colony forming unit | | dil-ac-LDL = 1,1'-dioctadecyl-3,3,3',3-tetramethyl-indocarbocyanine perchlorate labeled acetylated low-density lipoprotein | | eNOS = endothelial nitric oxide synthase | | EPC = endothelial progenitor cell | | FITC = fluorescein isothiocyanate | | HMG-CoA = 3-hydroxy-3-methyl-glutaryl coenzyme A | | NO = nitric oxide | | PBMC = peripheral blood mononuclear cells |
|
Related Article
-
ADMAring Endothelial Progenitor Cells: Accident, Association, or Antecedent
- Gajen Kanaganayagam and Michael S. Marber
J. Am. Coll. Cardiol. 2005 46: 1702-1704.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
K. Chobanyan-Jurgens, V. V. Pham, D. O. Stichtenoth, and D. Tsikas
Asymmetrical Dimethylarginine, Oxidative Stress, and Atherosclerosis
Hypertension,
November 1, 2011;
58(5):
e184 - e185.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. T. Jenkins, R. Q. Landers, S. J. Prior, N. Soni, E. E. Spangenburg, and J. M. Hagberg
Effects of acute and chronic endurance exercise on intracellular nitric oxide and superoxide in circulating CD34+ and CD34- cells
J Appl Physiol,
September 1, 2011;
111(3):
929 - 937.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T.-M. Lu, M.-Y. Chung, C.-C. Lin, C.-P. Hsu, and S.-J. Lin
Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease
Clin. J. Am. Soc. Nephrol.,
July 1, 2011;
6(7):
1566 - 1572.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Hamed, B. Brenner, and A. Roguin
Nitric oxide: a key factor behind the dysfunctionality of endothelial progenitor cells in diabetes mellitus type-2
Cardiovasc Res,
July 1, 2011;
91(1):
9 - 15.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Thum, K. Schmitter, F. Fleissner, V. Wiebking, B. Dietrich, J. D. Widder, V. Jazbutyte, S. Hahner, G. Ertl, and J. Bauersachs
Impairment of endothelial progenitor cell function and vascularization capacity by aldosterone in mice and humans
Eur. Heart J.,
May 2, 2011;
32(10):
1275 - 1286.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Heiss, A. Schanz, N. Amabile, S. Jahn, Q. Chen, M. L. Wong, T. Rassaf, Y. Heinen, M. Cortese-Krott, W. Grossman, et al.
Nitric Oxide Synthase Expression and Functional Response to Nitric Oxide Are Both Important Modulators of Circulating Angiogenic Cell Response to Angiogenic Stimuli
Arterioscler Thromb Vasc Biol,
November 1, 2010;
30(11):
2212 - 2218.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. Kielstein and D. Fliser
Do sea stars have low ADMA levels? High ADMA and low EPC count--duo infernal for the kidney
Nephrol. Dial. Transplant.,
October 1, 2010;
25(10):
3138 - 3141.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Surdacki, E. Marewicz, E. Wieczorek-Surdacka, T. Rakowski, G. Szastak, J. Pryjma, D. Dudek, and J. S. Dubiel
Synergistic effects of asymmetrical dimethyl-L-arginine accumulation and endothelial progenitor cell deficiency on renal function decline during a 2-year follow-up in stable angina
Nephrol. Dial. Transplant.,
August 1, 2010;
25(8):
2576 - 2583.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. P. Brandes
A miR-thless Perspective: How Asymmetric Dimethylarginine Impairs the Functions of Angiogenic Progenitor Cells
Circ. Res.,
July 9, 2010;
107(1):
12 - 14.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Fleissner, V. Jazbutyte, J. Fiedler, S. K. Gupta, X. Yin, Q. Xu, P. Galuppo, S. Kneitz, M. Mayr, G. Ertl, et al.
Short Communication: Asymmetric Dimethylarginine Impairs Angiogenic Progenitor Cell Function in Patients With Coronary Artery Disease Through a MicroRNA-21-Dependent Mechanism
Circ. Res.,
July 9, 2010;
107(1):
138 - 143.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. H. Huang, Y. H. Chen, H. Y. Tsai, J. S. Chen, T. C. Wu, F. Y. Lin, M. Sata, J. W. Chen, and S. J. Lin
Intake of Red Wine Increases the Number and Functional Capacity of Circulating Endothelial Progenitor Cells by Enhancing Nitric Oxide Bioavailability
Arterioscler Thromb Vasc Biol,
April 1, 2010;
30(4):
869 - 877.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. K. A. Shakoor, A. Aldibbiat, L. E. Ingoe, S. C. Campbell, L. Sibal, J. Shaw, P. D. Home, S. Razvi, and J. U. Weaver
Endothelial Progenitor Cells in Subclinical Hypothyroidism: The Effect of Thyroid Hormone Replacement Therapy
J. Clin. Endocrinol. Metab.,
January 1, 2010;
95(1):
319 - 322.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. R. Fiedler, T. Bachetti, J. Leiper, I. Zachary, L. Chen, T. Renne, and B. Wojciak-Stothard
The ADMA/DDAH Pathway Regulates VEGF-Mediated Angiogenesis
Arterioscler Thromb Vasc Biol,
December 1, 2009;
29(12):
2117 - 2124.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. T. Jenkins, S. Witkowski, E. E. Spangenburg, and J. M. Hagberg
Effects of acute and chronic endurance exercise on intracellular nitric oxide in putative endothelial progenitor cells: role of NAPDH oxidase
Am J Physiol Heart Circ Physiol,
November 1, 2009;
297(5):
H1798 - H1805.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Silvestre and B. I. Levy
Circulating progenitor cells and cardiovascular outcomes: latest evidence on angiotensin-converting enzyme inhibitors
Eur. Heart J. Suppl.,
August 1, 2009;
11(suppl_E):
E17 - E21.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Leone, M. Valgimigli, M. B. Giannico, V. Zaccone, M. Perfetti, D. D'Amario, A. G. Rebuzzi, and F. Crea
From bone marrow to the arterial wall: the ongoing tale of endothelial progenitor cells
Eur. Heart J.,
April 2, 2009;
30(8):
890 - 899.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-L. Balligand, O. Feron, and C. Dessy
eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues
Physiol Rev,
April 1, 2009;
89(2):
481 - 534.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-P. Diller, E. Bedard, S. J. Wort, M. A. Gatzoulis, S. van Eijl, O. Ali, M. R. Wilkins, J. Wharton, D. O. Okonko, L. S. Howard, et al.
Response to Letter Regarding Article, "Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension"
Circulation,
March 10, 2009;
119(9):
e231 - e231.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Pirro, G. Schillaci, P. F. Romagno, M. R. Mannarino, F. Bagaglia, R. Razzi, L. Pasqualini, G. Vaudo, and E. Mannarino
Influence of Short-term Rosuvastatin Therapy on Endothelial Progenitor Cells and Endothelial Function
Journal of Cardiovascular Pharmacology and Therapeutics,
March 1, 2009;
14(1):
14 - 21.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. S. Kostapanos, H. J. Milionis, and M. S. Elisaf
An Overview of the Extra-Lipid Effects of Rosuvastatin
Journal of Cardiovascular Pharmacology and Therapeutics,
September 1, 2008;
13(3):
157 - 174.
[Abstract]
[PDF]
|
|
|
|
|
|
|
F. Santilli, M. Romano, A. Recchiuti, A. Dragani, A. Falco, G. Lessiani, F. Fioritoni, S. Lattanzio, D. Mattoscio, R. De Cristofaro, et al.
Circulating endothelial progenitor cells and residual in vivo thromboxane biosynthesis in low-dose aspirin-treated polycythemia vera patients
Blood,
August 15, 2008;
112(4):
1085 - 1090.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Surdacki, E. Marewicz, E. Wieteska, G. Szastak, T. Rakowski, E. Wieczorek-Surdacka, D. Dudek, J. Pryjma, and J. S. Dubiel
Association between endothelial progenitor cell depletion in blood and mild-to-moderate renal insufficiency in stable angina
Nephrol. Dial. Transplant.,
July 1, 2008;
23(7):
2265 - 2273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-P. Diller, S. van Eijl, D. O. Okonko, L. S. Howard, O. Ali, T. Thum, S. J. Wort, E. Bedard, J. S. R. Gibbs, J. Bauersachs, et al.
Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension
Circulation,
June 10, 2008;
117(23):
3020 - 3030.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Dimmeler and A. Leri
Aging and Disease as Modifiers of Efficacy of Cell Therapy
Circ. Res.,
June 6, 2008;
102(11):
1319 - 1330.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Spinetti, N. Kraenkel, C. Emanueli, and P. Madeddu
Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies
Cardiovasc Res,
May 1, 2008;
78(2):
265 - 273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. F. Van Craenenbroeck, C. J. Vrints, S. E. Haine, K. Vermeulen, I. Goovaerts, V. F. I. Van Tendeloo, V. Y. Hoymans, and V. M. A. Conraads
A maximal exercise bout increases the number of circulating CD34+/KDR+ endothelial progenitor cells in healthy subjects. Relation with lipid profile
J Appl Physiol,
April 1, 2008;
104(4):
1006 - 1013.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Lucke, N. Kanzelmeyer, K. Chobanyan, D. Tsikas, D. Franke, M. J. Kemper, J. H.H. Ehrich, and A. M. Das
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.,
February 1, 2008;
23(2):
734 - 740.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Thum, F. Fleissner, I. Klink, D. Tsikas, M. Jakob, J. Bauersachs, and D. O. Stichtenoth
Growth Hormone Treatment Improves Markers of Systemic Nitric Oxide Bioavailability via Insulin-Like Growth Factor-I
J. Clin. Endocrinol. Metab.,
November 1, 2007;
92(11):
4172 - 4179.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Wilson, R. Harada, N. Nair, N. Balasubramanian, and J. P. Cooke
L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm
Circulation,
July 10, 2007;
116(2):
188 - 195.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. P. Fadini, S. Sartore, C. Agostini, and A. Avogaro
Significance of Endothelial Progenitor Cells in Subjects With Diabetes
Diabetes Care,
May 1, 2007;
30(5):
1305 - 1313.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. Kielstein and C. Zoccali
A New Perspective for the Treatment of Renal Diseases?
J. Am. Soc. Nephrol.,
May 1, 2007;
18(5):
1365 - 1367.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Thum, D. Fraccarollo, S. Thum, M. Schultheiss, A. Daiber, P. Wenzel, T. Munzel, G. Ertl, and J. Bauersachs
Differential Effects of Organic Nitrates on Endothelial Progenitor Cells Are Determined by Oxidative Stress
Arterioscler Thromb Vasc Biol,
April 1, 2007;
27(4):
748 - 754.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Konishi, K. Sydow, and J. P. Cooke
Dimethylarginine Dimethylaminohydrolase Promotes Endothelial Repair After Vascular Injury
J. Am. Coll. Cardiol.,
March 13, 2007;
49(10):
1099 - 1105.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Thum, D. Fraccarollo, M. Schultheiss, S. Froese, P. Galuppo, J. D. Widder, D. Tsikas, G. Ertl, and J. Bauersachs
Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes
Diabetes,
March 1, 2007;
56(3):
666 - 674.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Shantsila, T. Watson, and G. Y.H. Lip
Endothelial Progenitor Cells in Cardiovascular Disorders
J. Am. Coll. Cardiol.,
February 20, 2007;
49(7):
741 - 752.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Thum, S. Hoeber, S. Froese, I. Klink, D. O. Stichtenoth, P. Galuppo, M. Jakob, D. Tsikas, S. D. Anker, P. A. Poole-Wilson, et al.
Age-Dependent Impairment of Endothelial Progenitor Cells Is Corrected by Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1
Circ. Res.,
February 16, 2007;
100(3):
434 - 443.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Andreotti, G. Coluzzi, A. Lavorgna, F. Marzo, E. Di Stasio, C. Carrozza, C. Zuppi, and F. Crea
Relation between nitric oxide metabolites and haemoglobin concentrations in patients with ischaemic heart disease
Heart,
February 1, 2007;
93(2):
255 - 257.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Leor and M. Marber
Endothelial Progenitors: A New Tower of Babel?
J. Am. Coll. Cardiol.,
October 17, 2006;
48(8):
1588 - 1590.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. X. Ma, B. Zhou, Z. Chen, Q. Ren, S. H. Lu, T. Sawamura, and Z. C. Han
Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase
J. Lipid Res.,
June 1, 2006;
47(6):
1227 - 1237.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Thum, D. Fraccarollo, P. Galuppo, D. Tsikas, S. Frantz, G. Ertl, and J. Bauersachs
Bone marrow molecular alterations after myocardial infarction: Impact on endothelial progenitor cells
Cardiovasc Res,
April 1, 2006;
70(1):
50 - 60.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Thum and J. Bauersachs
ADMA, Endothelial Progenitor Cells, and Cardiovascular Risk
Circ. Res.,
October 14, 2005;
97(8):
e84 - e84.
[Full Text]
[PDF]
|
|
|
|
