Asymmetric dimethylarginine induces tissue factor expression in monocytes via NF-kappaB-dependent pathway: Role in...

Asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of nitric oxide synthase, is recently defined as an independent cardiovascular risk factor. Tissue factor (TF) expression and procoagulant activity (PCA) of peripheral monocytes are increased in patients with acute coronary syndromes (ACS), which resulted in blood procoagulant state tending to thrombus formation. In the present study, we tested the hypothesis that ADMA contribute to TF expression of peripheral monocytes in ACS. Twenty patients with unstable angina (UA), 20 patients with stable angina (SA) and 20 control subjects were recruited. Monocytic cell line THP-1 was incubated with different concentrations of ADMA (1-10microM) for various periods (6-24h). Our results showed that plasma level of ADMA in patients with UA was significantly higher than those in patients with SA or in the control group, and positively correlated with TF antigen level and PCA of circulating monocytes. Adjusting for all patient characteristics, we confirmed these findings in multivariate regression analyses. In cultured THP-1 cells, ADMA transcriptionally upregulated both TF antigen expression and PCA in a concentration-dependent manner. The experiments using nuclear factor-kappaB (NF-kappaB) inhibitor and transient transfection with wild-type and mutated TF promotor constructs showed that the NF-kappaB is an important transcriptional regulator of ADMA-induced TF expression. Our results suggest that elevated plasma level of ADMA induces TF expression in monocytes via NF-kappaB-dependent pathway, which contributes to procoagulant phenotype of circulating monocytes in ACS.