Statins attenuate thrombin‐stimulated tissue factor expression on human endothelial cells through regulation of cJun

Abstract

Statins decrease agonist-stimulated expression of the procoagulant protein tissue factor (TF) in human endothelial cells, but the signaling pathways affected by statins have not been clearly delineated. We previously showed that thrombin promotes the increased expression of TF on human endothelial cells through increased expression of cFos and increased phosphorylation of cJun, components of the AP1 transcription factor. When human endothelial cells were pretreated overnight with 1 μM fluvastatin or simvastatin, thrombin (2 U/ml) stimulation of TF expression was greatly attenuated. Statin pretreatment did not significantly affect the expression of cFos, but decreased the expression of cJun. Moreover, cJun activation by its upstream regulator c-Jun NH2-terminal kinase (JNK) was greatly attenuated. Thus, fluvastatin and simvastatin impede the expression of TF in human endothelial cells through regulation of the AP1 transcription factor component cJun: cJun expression is reduced and its activation is diminished due to the decreased activity of the stress-activated kinase JNK. These studies demonstrate that statins can serve as potent pharmacological inhibitors of the JNK/cJun pathway in a pleiotropic, non-cholesterol dependent manner. This, then, provides a novel mechanism for statin-mediated reduction in thrombotic events. This research was supported by an AHA grant.