Proteasome Inhibitors Enhance Endothelial Thrombomodulin Expression via Induction of Kruppel-Like Transcription Factors

Department of Medicine, Johns Hopkins School of Medicine, Ross 1165, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 09/2009; 29(10):1587-93. DOI: 10.1161/ATVBAHA.109.191957
Source: PubMed

ABSTRACT 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.
These findings identify a novel mechanism of action of proteasome inhibitors that may help to explain their clinically observed thromboprotective effects.

Download full-text


Available from: Toyoko Hiroi, Sep 26, 2015
23 Reads
  • Source
    • "When a combination of Len/Dex/Bor is applied in the clinic, Bor does not seem to accelerate the thrombotic tendency associated with Len/Dex [21]. Hiroi et al. reported that proteasome inhibitors such as Bor enhanced the expression of an anticoagulant glycoprotein thrombomodulin in endothelial cells [22]. However, we did not observe an enhancement of thrombomodulin expression in the cells that we used (data not shown). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the procoagulant effects of lenalidomide (Len)-based regimens in vitro focusing on tissue factor (TF) and phosphatidylserine (PS). We examined the effects of a pharmacological concentration of Len with or without the corticosteroid dexamethasone (Dex) and the proteasome inhibitor bortezomib (Bor) using the human vascular endothelial cell line EAhy926 and the monocytic cell lines THP-1 and U937. Cell-surface procoagulant activity (PCA) was induced by Dex-containing regimens in all lines. Expression of TF antigen on the cell surface and of TF mRNA was markedly increased by Dex-containing regimens. PS exposure was increased modestly by a Len-based regimen. PS exposure was increased modestly in EAhy926 cells, and markedly increased in THP-1 and U937 cells by Bor-containing treatment. An anti-TF monoclonal antibody almost completely blocked the induced PCA. When Len is given in combination with Dex, PCA may be induced on endothelial cells and monocytes through TF expression and PS exposure.
    PLoS ONE 05/2013; 8(5):e64369. DOI:10.1371/journal.pone.0064369 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Kruppel-like factor 2 (KLF2) and Kruppel-like factor 4 (KLF4) transcription factors have recently been shown to act as critical regulators of endothelial homeostasis. While several insights have been made into the signaling mechanisms orchestrating endothelial KLF2 expression, those governing the expression of KLF4 in the vascular endothelium remain largely unknown. Here, we show that diverse vasoprotective stimuli including an atheroprotective shear stress waveform, simvastatin, and resveratrol induce the expression of KLF4 in cultured human endothelial cells. We further demonstrate that the induction of KLF4 by resveratrol and atheroprotective shear stress occurs via a MEK5/MEF2-dependent signaling pathway. Since MEK5 activation is also critical for the expression of KLF2, we assessed the individual contribution of KLF4 and KLF2 to the global transcriptional activity triggered by MEK5 activation. Genome-wide transcriptional profiling of endothelial cells overexpressing KLF4, KLF2, or constitutively active MEK5 revealed that 59.2% of the genes regulated by the activation of MEK5 were similarly controlled by either KLF2 or KLF4. Collectively, our data identify a significant degree of mechanistic and functional conservation between KLF2 and KLF4, and importantly, provide further insights into the complex regulatory networks governing endothelial vasoprotection.
    Biochemical and Biophysical Research Communications 01/2010; 391(1-391):984-989. DOI:10.1016/j.bbrc.2009.12.002 · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with multiple myeloma are at increased risk of venous thromboembolism (VTE) compared to the general population. The introduction of immunomodulatory agents, such as thalidomide and lenalidomide, substantially increases the incidence of VTE in multiple myeloma patients, especially when used in combination with high-dose dexamethasone and/or anthracycline-based chemotherapy. Thromboprophylaxis is recommended for reducing VTE in patients receiving immunomodulatory agent-based regimens. On the other hand, bortezomib, a proteasome inhibitor, is not associated with an increased risk of VTE, as observed by a very low incidence of thrombotic complications in the absence of thromboprophylaxis. Currently, the mechanisms underlying the impact of these agents on VTE are not well-understood. Further studies to investigate the pathogenesis of VTE in multiple myeloma are warranted. These studies may not only yield greater insight into the pathogenesis of disease but may also define novel targets for the prevention and treatment of thromboembolic events in patients with multiple myeloma.
    European journal of cancer (Oxford, England: 1990) 04/2010; 46(10):1790-9. DOI:10.1016/j.ejca.2010.03.007 · 5.42 Impact Factor
Show more