system
Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, RESULTS. Meshes: Animals, Boronic Acids, Bortezomib, Cells, Cultured, Endothelial Cells, Humans, Kruppel-Like Transcription Factors, Male, Mice, Mice, Inbred C3H, NF-kappa B, Protease Inhibitors, Proteasome Inhibitors, Protein C, Pyrazines, Thrombomodulin.
user
Do proteasome inhibitors enhance endothelial thrombomodulin expression via induction of Krüppel-like transcription factors? Context: Impairment of the thrombomodulin-protein C anticoagulant pathway has been implicated in pathological thrombosis associated with malignancy. Patients who receive proteasome inhibitors as part of their chemotherapeutic regimen appear to be at decreased risk for thromboembolic events. We investigated the effects of proteasome inhibitors on endothelial thrombomodulin expression and function. Proteasome inhibitors as a class markedly induced the expression of thrombomodulin and enhanced the protein C activating capacity of endothelial cells. Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. These effects were confirmed in vivo, where systemic administration of a proteasome inhibitor enhanced thrombomodulin expression that was paralleled by changes in the expression of KLF2 and KLF4.
assistant
These findings identify a novel mechanism of action of proteasome inhibitors that may help to explain their clinically observed thromboprotective effects. Final Decision: yes