Increased asymmetric dimethylarginine concentrations in stimulated peripheral blood mononuclear cells

Elevated concentrations of total homocysteine as well as of asymmetric dimethylarginine (ADMA) in the blood have been reported to reflect an increased cardiovascular risk. ADMA is formed by endothelial cells and is an endogenous inhibitor of NO synthase. Earlier we have found that human peripheral blood mononuclear cells (PBMC) produce homocysteine upon stimulation with mitogens concanavalin A, phytohaemagglutinin and pokeweed mitogen. In this study, the ability of PBMC to form ADMA and symmetric dimethylarginine (SDMA) was determined. Effects were compared with levels of cysteine, homocysteine and arginine in cultures. Increased concentrations of ADMA and SDMA were found in mitogen-stimulated compared with unstimulated PBMC. Arginine and cysteine concentrations did not differ between stimulated and unstimulated PBMC. There existed significant associations between concentrations of homocysteine and ADMA (Spearman rank correlation (rs) = 0.575) as well as SDMA (rs = 0.436, both P < 0.001). Treatment of stimulated PBMC with the anti-inflammatory compounds salicylic acid (5 mm) and atorvastatin (25 microm) decreased the rate of ADMA and SDMA formation. Results of these in vitro studies show that ADMA and SDMA formation coincides with homocysteine production in human PBMC. Activated PBMC not only release Th1-type cytokine gamma-interferon, which is the most important inducer of nitric oxide synthase, but also ADMA, a natural inhibitor of the enzyme.