Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 29, Issue 10, Pages 1587-U458Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.109.191957
Keywords
proteasome inhibitor; thrombomodulin; Kruppel-like transcription factor; protein C; thrombosis
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Funding
- Millennium Pharmaceuticals Inc
- National Institutes of Health [HL080142, HL-07227]
- American Heart Association [DOD 903687]
- Malaria Institute of Bloomberg School of Public Health
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL080142, T32HL007227] Funding Source: NIH RePORTER
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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 and Results-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-kappa B signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Kruppel-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. (Arterioscler Thromb Vasc Biol. 2009;29:1587-1593.)
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