CLINICAL RESEARCH
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.
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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 |
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