Anticoagulant effect of wogonin against tissue factor expression.

ABSTRACT

Tissue factor (TF) is the primary cause of atherothrombosis, the rupture of atherosclerotic plaques with subsequent thrombosis, leading to acute cardiovascular events, such as myocardial infarction and stroke. Wogonin (Wog) is an active component of Scutellaria baicalensis, used for inflammatory diseases, atherosclerosis, and hyperlipidemia. The anticoagulant effect of Wog on TF expression remains unexplored. In this study, we have investigated the effects of Wog on TF gene expression and its underlying molecular mechanism in human vascular endothelial cells (ECs). We found that Wog dose-dependently inhibited PMA-enhanced TF mRNA, protein, and activity in ECs. This inhibition was attributed to its decreasing nuclear accumulations of transcription factors, phospho-c-Jun and early growth response-1(Egr-1), not nuclear factor-κB (NF-κB), through blocking extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways. Reduction by Wog of Egr-1 nuclear level and Egr-1/DNA binding activity was associated with its inhibition of Egr-1 de novo synthesis. Wog as well as inhibitors to ERK and JNK suppressed TF promoter activity and protein expression in reporter gene and Western blot analyses. Furthermore, it also exhibited anticoagulant function by inhibiting TF expression and activity in tumor necrosis factor-alpha (TNF-α)- and lipopolysaccharide (LPS)-treated ECs and THP-1 cells. These results suggest that Wog inhibits ERK/Egr-1- and JNK/AP-1-mediated transactivation of TF promoter activity, leading to downregulation of TF expression and activity induced by inflammatory mediators. Wog targeting pathological TF expression without affecting its basal level may be a safer templet in the development of anticoagulant agent for cardiovascular thrombotic diseases related to atherothrombosis.