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J. Biol. Chem., Vol. 282, Issue 39, 28408-28418, September 28, 2007

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Histone Deacetylase Inhibitors Suppress TF-B-dependent Agonist-driven Tissue Factor Expression in Endothelial Cells and Monocytes^*

Jianguo Wang^¶, Shawn A. Mahmud^¶, Peter B. Bitterman^||, Yuqing Huo^¶**, and Arne Slungaard^¶1

From the Sections of Hematology, Oncology, and Transplantation, ^||Pulmonary and Critical Care, and ^**Cardiology, Medicine Department, and the ^¶Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota 55455

Histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA), can regulate gene expression by promoting acetylation of histones and transcription factors. Human tissue factor (TF) expression is partly governed by a unique, NF-B-related "TF-B" promoter binding site. We find that TSA and four other HDACi (apicidin, MS-275, sodium butyrate, and valproic acid) all inhibit by 90% TF activity and protein level induction in human umbilical vein endothelial cells stimulated by the physiologic agonists tumor necrosis factor (TNF)-, interleukin-1, lipopolysaccharide, and HOSCN without affecting expression of the NF-B-regulated adhesion molecules ICAM-1 and E-selectin. TSA and butyrate also blunt TF induction 50% in vitro in peripheral blood mononuclear cells and in vivo in thioglycolate-elicited murine peritoneal macrophages. In human umbilical vein endothelial cells, TSA attenuates by 70% TNF- stimulation of TF mRNA transcription without affecting that of ICAM-1. By electrophoretic mobility shift assay analyses, TNF- and lipopolysaccharide induce strong p65/p50 and p65/c-Rel heterodimer binding to both NF-B and TF-B probes. TSA nearly abolishes TF-B binding without affecting NF-B binding. A chromatin immunoprecipitation assay and a promoter-luciferase reporter system confirm that TSA inhibits TF-B but not NF-B activation. Chromatin immunoprecipitation and small interfering RNA inhibitor studies demonstrate that HDAC3 plays a significant role in TNF--mediated TF induction. Thus, HDACi transcriptionally inhibit agonist-induced TF expression in endothelial cells and monocytes by a TF-B- and HDAC3-dependent mechanism. We conclude that histone deacetylases, particularly HDAC3, play a hitherto unsuspected role in regulating TF expression and raise the possibility that HDACi might be a novel therapy for thrombotic disorders.

Received for publication, May 1, 2007 , and in revised form, August 2, 2007.

^* This work was supported by National Institutes of Health Grants HL-070937 (to A. S.) and HL-078679 (to Y. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Mayo Mail Code 480; 420 Delaware St. S.E., Minneapolis, MN 55455. Tel.: 612-624-9410; Fax: 612-625-6919; E-mail: slung001{at}umn.edu.

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