Involvement of DDAH/ADMA pathway in the pathogenesis of rheumatoid arthritis in rats

Int Immunopharmacol. 2013 Jun;16(2):322-31. doi: 10.1016/j.intimp.2013.04.009. Epub 2013 Apr 22.


Endothelial dysfunction is the early stage of atherosclerosis, which is typically associated with rheumatoid arthritis (RA), a chronic inflammatory autoimmune disorder. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is not only an independent predictor for endothelial dysfunction but also a proinflammatory mediator. It has been shown that the level of ADMA was elevated in patients with RA. In the present study, we investigated the potential effect of ADMA on inflammation process in collagen-induced arthritis (CIA) animal model and primary cultured fibroblast-like synoviocytes (FLS) exposed to tumor necrosis factor-α (TNF-α). In CIA rats, the plasma levels of inflammatory cytokines TNF-α, interleukin-1β (IL-1β) and IL-6 were markedly increased, while the plasma levels of ADMA did not increase. The expression of dimethylarginine dimethylohydrolase2 (DDAH2), the key enzyme for ADMA degradation, was markedly reduced in inflamed joint synovium of CIA rats. Moreover, the expression of anti-inflammatory factor cortistatin (CST) was markedly decreased in joint synovium of CIA rats. Treatment of cultured FLS with TNF-α significantly increased the levels of ADMA, and decreased the expression of DDAH2 mRNA and protein accompany with an increase in the levels of IL-1β and IL-6 and a reduction in the expression of CST mRNA and protein, and the effects of TNF-α were abolished by DDAH2 overexpression. Treatment of FLS with ADMA also significantly increased the levels of IL-1β and IL-6, and reduced the expression of CST. These findings suggest that DDAH/ADMA participates in the pathogenesis of RA, and that the effect of DDAH/ADMA may be mediated by CST.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / genetics
  • Amidohydrolases / immunology*
  • Animals
  • Ankle Joint / pathology
  • Arginine / analogs & derivatives*
  • Arginine / immunology
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / pathology
  • Cytokines / blood
  • Cytokines / genetics
  • Male
  • Neuropeptides / immunology*
  • Rats
  • Rats, Sprague-Dawley
  • Synovial Membrane / immunology
  • Synovial Membrane / pathology


  • Cytokines
  • Neuropeptides
  • cortistatin
  • N,N-dimethylarginine
  • Arginine
  • Amidohydrolases
  • dimethylargininase