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
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Figure 1 Inverse correlation of plasma asymmetric dimethylarginine (ADMA) and CD34+/CD133+ progenitor cells in patients with coronary artery disease. The ADMA plasma levels (A) and circulating CD34+/CD133+ progenitor cells (B) in patients who underwent coronary angiography. CAD 0 = no coronary artery disease; CAD 1 = one-vessel disease; CAD 2 = two-vessel disease; CAD 3 = three-vessel disease. (C) Correlation between circulating CD34+/CD133+ progenitor cells or endothelial colony-forming units (CFUs) (D) with the concentration of plasma ADMA levels in patients with different severity of coronary artery disease (Table 1).
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Figure 2 Inhibition of endothelial progenitor cells by asymmetric dimethylarginine (ADMA). Adherent 1,1'-dioctadecyl-3,3,3',3-tetramethyl-indocarbocyanine perchlorate labeled acetylated low-density lipoprotein (dil-ac-LDL)/fluorescein isothiocyanate labeled Ulex euroneus lectin-1 (UEA-1-FITC) double-positive cells after treatment of peripheral blood mononuclear cells with increasing concentrations (1 to 10 µmol) of ADMA and ADMA + rosuvastatin (RSV) (10 µmol/l) for four days (each n = 5). Cells were counted in at least eight independent randomly selected high-power fields by two investigators.
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Figure 3 Asymmetric dimethylarginine (ADMA) reduces the amount and size of colony-forming units. Amount (A) and size (B) of colony-forming units after treatment of peripheral blood mononuclear cells with increasing concentrations of ADMA and ADMA + rosuvastatin (RSV) (each n = 5).
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Figure 4 Asymmetric dimethylarginine (ADMA) inhibits incorporation of endothelial progenitor cells (EPCs) in tube-like structures. Incorporation of EPCs (labeled with 1,1'-dioctadecyl-3,3,3',3-tetramethyl-indocarbocyanine perchlorate labeled acetylated low-density lipoprotein [dil-ac-LDL]; red) in forming endothelial tubes from human umbilical vein endothelial cells (HUVECs) (labeled with UEA1-FITC; green) after treatment with increasing concentrations of ADMA or ADMA + rosuvastatin (RSV) (each n = 5). Two investigators in blinded experiments examined eight randomly selected high-power fields per experiment.
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Figure 5 Asymmetric dimethylarginine (ADMA) inhibits endothelial nitric oxide synthase (eNOS) activity in endothelial progenitor cells (EPCs). The eNOS activity was determined in EPC cell culture supernatants by assessing the conversion of L-[guanidino-15N2]arginine to 15N-nitrate with gas chromatography/mass spectrometry. The 15N-nitrate/14N-nitrate ratio is shown. RSV = rosuvastatin.
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