title: Elevated plasma asymmetric dimethyl-L-arginine levels are linked to endothelial progenitor cell depletion and carotid atherosclerosis in rheumatoid arthritis.
abstract: OBJECTIVE
  Similarities between rheumatoid arthritis (RA) and atherosclerosis include endothelial dysfunction (an antecedent of plaque formation) and depletion of circulating bone marrow-derived endothelial progenitor cells. This study was undertaken to test the hypothesis that endothelial progenitor cell depletion and subclinical atherosclerosis in RA may be related to accumulation of an endogenous inhibitor of nitric oxide (NO) synthesis, asymmetric dimethyl-L-arginine.
  
  
  METHODS
  We studied 30 patients with active RA and 20 age- and sex-matched healthy controls. Exclusion criteria were clinically evident atherosclerosis, traditional risk factors, hyperhomocysteinemia, and renal dysfunction. The blood endothelial progenitor cell count was assayed by flow cytometry and expressed as a percentage of lymphocytes. Plasma L-arginine, asymmetric dimethyl-L-arginine, and symmetric dimethyl-L-arginine were measured with liquid chromatography-mass spectrometry. Mean carotid intima-media thickness (IMT) was assessed by B-mode ultrasound.
  
  
  RESULTS
  In RA patients, we found elevated levels of asymmetric dimethyl-L-arginine (mean +/- SD 0.49 +/- 0.07 micromoles/liter versus 0.40 +/- 0.07 micromoles/liter in controls; P < 0.001), a depressed endothelial progenitor cell count (0.039 +/- 0.025% versus 0.063 +/- 0.035%; P < 0.05), and increased IMT (0.65 +/- 0.13 mm versus 0.55 +/- 0.10 mm; P < 0.01), with no differences in levels of L-arginine or symmetric dimethyl-L-arginine. The endothelial progenitor cell count was inversely correlated with the level of asymmetric dimethyl-L-arginine. IMT was positively related to the ratio of asymmetric dimethyl-L-arginine to L-arginine and negatively related to the endothelial progenitor cell count, in univariate and multivariate analyses.
  
  
  CONCLUSIONS
  Plasma asymmetric dimethyl-L-arginine levels are elevated in RA patients free of cardiovascular disease or risk factors. Asymmetric dimethyl-L-arginine accumulation may contribute to endothelial progenitor cell depletion via depressed NO-dependent endothelial progenitor cell mobilization and/or survival, with consequent impairment of endothelial progenitor cell-mediated endothelial repair, which can promote atherogenesis in RA.
authors.affiliation: Jagiellonian University, Cracow, Poland. surdacki.andreas@gmx.net
authors.forename: Andrzej
authors.initials: A
authors.lastname: Surdacki
authors.forename: Jens
authors.initials: J
authors.lastname: Martens-Lobenhoffer
authors.forename: Alicja
authors.initials: A
authors.lastname: Wloch
authors.forename: Ewa
authors.initials: E
authors.lastname: Marewicz
authors.forename: Tomasz
authors.initials: T
authors.lastname: Rakowski
authors.forename: Ewa
authors.initials: E
authors.lastname: Wieczorek-Surdacka
authors.forename: Jacek S
authors.initials: JS
authors.lastname: Dubiel
authors.forename: Juliusz
authors.initials: J
authors.lastname: Pryjma
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Bode-Böger
mesh_terms: D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000473:pathology; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000473:pathology; D002340:Carotid Artery Diseases / Q000209:etiology* / Q000473:pathology; D016022:Case-Control Studies; D002452:Cell Count; D042783:Endothelial Cells / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine