Asymmetric Dimethyl Arginine as a Biomarker of Atherosclerosis in Rheumatoid Arthritis

Figure 2

Mechanisms of ADMA-induced endothelial dysfunction in rheumatoid arthritis. The inflammatory microenvironment of the inflamed synovia produces cytokines and reactive oxygen species which directly stimulate PRTM and inhibits DDAH in endothelial cells, increasing ADMA production. Cytokines influence metabolically active tissues like skeletal muscle and adipocytes, inducing insulin resistance. This can generate a positive feedback loop, with an increased release of cytokines from macrophages and increased ADMA production in endothelial cells as well. The increased levels of oxidated lipoproteins, as a consequence of the oxidative stress linked to synovitis, furthermore contribute to ADMA synthesis, as well as the increased apoptosis of endothelial cells in inflamed synovium. At last, folate deficit, related to the increased cellular turnover, to the oxidation of folate from reactive oxygen species and to the methotrexate treatment, induces an increased generation of homocysteine, which contributes to ADMA increase. ADMA increase can induce endothelial dysfunction, oxidative stress, and EPCs inhibition, conducing atherosclerosis development and cardiovascular complications. PRMT: protein arginine methyltransferases; DDAH: dimethylarginine dimethylaminohydrolase; NOS: nitric oxide synthase; ADMA: asymmetric dimethyl arginine; EPCs: endothelial progenitor cells; MTX: methotrexate; Hcy: homocysteine; CVD: cardiovascular disease.