Genetic regulation of dimethylarginines and endothelial dysfunction in rheumatoid arthritis

Abstract

Rheumatoid Arthritis (RA) confers an increased cardiovascular disease (CVD) risk which accounts for much of the premature morbidity and mortality observed in this population. Alterations in vascular function and morphology leading to increased atherosclerotic burden are considered the main drivers of CVD in RA individuals with systemic inflammation playing a key role in the dysregulation of endothelial homeostasis and initiation of vascular injury. Dimethylarginines are endogenous inhibitors of nitric oxide (NO) synthase and have emerged as novel, independent biomarkers of CVD in a wide range of conditions associated with vascular pathology. In RA several reports have demonstrated abnormal dimethylarginine metabolism attributable to various factors such as systemic inflammation, decreased degradation or upregulated synthesis. Although a causal relationship between dimethylarginines and vascular damage in RA has not been established, the tight interrelations between inflammation, dimethylarginines and endothelial dysfunction suggest that determination of dimethylarginine regulators may shed more light in the pathophysiology of the atherosclerotic process in RA and may also provide new therapeutic targets. The Alanine–Glyoxylate Aminotransferase 2 (AGTX2)-dependent pathway is a relatively recently discovered alternative pathway of dimethylarginine catabolism and its role on RA-related atherosclerotic disease is yet to be established. As factors affecting dimethylarginine concentrations linked to CVD risk and endothelial dysfunction are of prominent clinical relevance in RA, we present preliminary evidence that gene variants of AGTX-2 may influence dimethylarginine levels in RA patients and provide the rationale for larger studies in this field.