Abstract 14409: Rosiglitazone Suppresses Tissue Factor Expression in Vascular Cells: A Promising Answer to Rosiglitazone Controversy
Objective: Rosiglitazone has various beneficial actions on vascular cells, but a potential role in coagulation has not been studied. Tissue factor (TF) is the primary molecule that initiates coagulation cascade and then triggers thrombus formation. We investigated the effect of rosiglitazone on tissue factor expression and elucidated its underlying mechanisms.
Methods and Results: Rosiglitazone inhibited TF expression in response to tumor necrosis factor-α in a concentration-dependent manner in three main cell types participating in vascular thrombus formation, which are human umbilical vein endothelial cells (HUVECs), human acute monocytic leukemia cell line (THP-1) and human umbilical vein smooth muscle cells (SMCs). The overexpression of TF was mediated by increased phosphorylation of MAP kinase, which was blocked by rosiglitazone. The main MAP kinase varied depending on cell types; HUVECs appeared to be dependent on JNK; THP-1, dependent on p38 and ERK; SMCs, dependent on JNK and p38. Luciferase and ChIP assays demonstrated that AP-1 might be a pivotal transcription factor for TF-lowering effect of rosiglitazone. TF expression in response to thrombin was exaggerated by the addition of paclitaxel, one of the most widely used drugs for drug-eluting stent. And again, rosiglitazone decreased paclitaxel-induced TF expression in all cell types. In contrast to the effect on TF, rosiglitazone did not decrease the expression of TF pathway inhibitor (TFPI) in HUVECs and moreover, it increased the TFPI expressions in THP-1 and SMCs. In rat carotid artery balloon injury model with paclitaxel infusion through intravascular pump, rosiglitazone attenuated TF expression which was induced by paclitaxel and increased TFPI expression in the injured vasculature.
Conclusions: Rosiglitazone suppressed TF expression by inhibitons of MAP kinase pathway and AP-1 binding activity. And it also reversed paclitaxel-induced aggravation of TF expression. These results might provide an answer to the concern about the cardiovascular safety of rosiglitazone and more interestingly, a possibility for clinical application of rosiglitazone as a therapeutic option to prevent stent thrombosis in patients treated with paclitaxel-eluting stents.
- © 2010 by American Heart Association, Inc.