Elevated levels of plasma symmetric dimethylarginine and increased arginase activity as potential indicators of cardiovascular comorbidity in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) patients are at high risk of developing cardiovascular disease (CVD). In RA, chronic inflammation may lead to endothelial dysfunction, an early indicator of CVD, owing to diminished nitric oxide (NO) production. Because L-arginine is the sole precursor of NO, we hypothesized that levels of L-arginine metabolic products reflecting NO metabolism are altered in patients with RA. Methods: Plasma samples from patients with RA (n = 119) and age-and sex-matched control subjects (n = 238) were used for this study. Using LC-MS/MS, we measured plasma levels of free L-arginine, L-ornithine, L-citrulline, L-NG-monomethyl arginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). We compared global arginine bioavailability ratio (GABR) (i.e., ratio of L-arginine to L-ornithine + L-citrulline) and arginine methylation index (ArgMI) (i.e., ADMA + SDMA/MMA) in patients with RA vs. control subjects. Plasma arginase activity was measured using a sensitive arginase assay kit. The relationship of L-arginine metabolites and arginase activity to CVD risk factors was evaluated using Pearson's chi-square test. Results: Compared with healthy control subjects, the RA cohort showed significantly lower levels of plasma L-arginine (46.11 +/- 17.29 vs. 74.2 +/- 22.53 mu mol/L, p < 0.001) and GABR (0.36 +/- 0.16 vs. 0.73 +/- 0.24, p < 0.001), elevated levels of ADMA (0.76 +/- 0.12 vs. 0.62 +/- 0.12 mu mol/L, p < 0.001), SDMA (0.54 +/- 0.14 vs. 0.47 +/- 0.13 mu mol/L, p < 0.001), and ArgMI (6.51 +/- 1.86 vs. 5.54 +/- 1.51, p < 0.001). We found an approximately fourfold increase in arginase activity (33.8 +/- 1.1 vs. 8.4 +/- 0.8 U/L, p < 0.001), as well as elevated levels of arginase-mediated L-arginine catalytic product L-ornithine (108.64 +/- 30.26 vs. 69.3 +/- 20.71 mu mol/L, p < 0.001), whereas a nitric oxide synthase (NOS) catalytic product, the L-citrulline level, was diminished in RA (30.32 +/- 9.93 vs. 36.17 +/- 11.64 mu mol/L, p < 0.001). Patients with RA with existing CVD had higher arginase activity than patients with RA without CVD (p = 0.048). Conclusions: Global L-arginine bioavailability was diminished, whereas plasma arginase activity, ADMA, and SDMA levels were elevated, in patients with RA compared with healthy control subjects. Plasma SDMA was associated with hypertension and hyperlipidemia in patients with RA. This dysregulated L-arginine metabolism may function as a potential indicator of CVD risk in patients with RA.