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

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. 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-N -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. 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 μmol/L, p