Proteasome inhibitors enhance endothelial thrombomodulin expression via induction of Krüppel-like transcription factors.
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.


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-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.
Hiroi
Toyoko
T
Department of Medicine, Johns Hopkins School of Medicine, Ross 1165, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Deming
Clayton B
CB
Zhao
Haige
H
Hansen
Baranda S
BS
Arkenbout
Elisabeth K
EK
Myers
Thomas J
TJ
McDevitt
Michael A
MA
Rade
Jeffrey J
JJ
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011486:Protein C / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*; D018180:Thrombomodulin / Q000235:genetics* / Q000502:physiology
D001897:Boronic Acids; C096161:KLF2 protein, human; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011486:Protein C; D011719:Pyrazines; D018180:Thrombomodulin; D000069286:Bortezomib