title: Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine.
abstract: OBJECTIVE
  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.
authors.affiliation: Bayerische Julius-Maximilians-Universität, Medizinische Klinik I, Würzburg, Germany. thum_t@medizin.uni-wuerzburg.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stein
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schultheiss
authors.forename: Martin
authors.initials: M
authors.lastname: Eigenthaler
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
authors.forename: Philip A
authors.initials: PA
authors.lastname: Poole-Wilson
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D002452:Cell Count; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D013234:Stem Cells / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; C018524:N,N-dimethylarginine; D001120:Arginine