Proteasome inhibitors enhance endothelial thrombomodulin expression via induction of Krüppel-like transcription factors.
Arterioscler Thromb Vasc Biol
; 29(10): 1587-93, 2009 Oct.
Article
en En
| MEDLINE
| ID: mdl-19661484
ABSTRACT
OBJECTIVE:
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. METHODS ANDRESULTS:
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.CONCLUSIONS:
These findings identify a novel mechanism of action of proteasome inhibitors that may help to explain their clinically observed thromboprotective effects.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Inhibidores de Proteasas
/
Pirazinas
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Ácidos Borónicos
/
Trombomodulina
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Células Endoteliales
/
Factores de Transcripción de Tipo Kruppel
/
Inhibidores de Proteasoma
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Asunto de la revista:
ANGIOLOGIA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos