Source:http://linkedlifedata.com/resource/pubmed/id/17675290
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
39
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pubmed:dateCreated |
2007-9-24
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pubmed:abstractText |
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-kappaB-related "TF-kappaB" promoter binding site. We find that TSA and four other HDACi (apicidin, MS-275, sodium butyrate, and valproic acid) all inhibit by approximately 90% TF activity and protein level induction in human umbilical vein endothelial cells stimulated by the physiologic agonists tumor necrosis factor (TNF)-alpha, interleukin-1beta, lipopolysaccharide, and HOSCN without affecting expression of the NF-kappaB-regulated adhesion molecules ICAM-1 and E-selectin. TSA and butyrate also blunt TF induction approximately 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 approximately 70% TNF-alpha stimulation of TF mRNA transcription without affecting that of ICAM-1. By electrophoretic mobility shift assay analyses, TNF-alpha and lipopolysaccharide induce strong p65/p50 and p65/c-Rel heterodimer binding to both NF-kappaB and TF-kappaB probes. TSA nearly abolishes TF-kappaB binding without affecting NF-kappaB binding. A chromatin immunoprecipitation assay and a promoter-luciferase reporter system confirm that TSA inhibits TF-kappaB but not NF-kappaB activation. Chromatin immunoprecipitation and small interfering RNA inhibitor studies demonstrate that HDAC3 plays a significant role in TNF-alpha-mediated TF induction. Thus, HDACi transcriptionally inhibit agonist-induced TF expression in endothelial cells and monocytes by a TF-kappaB- 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.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/E-Selectin,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylases,
http://linkedlifedata.com/resource/pubmed/chemical/Histones,
http://linkedlifedata.com/resource/pubmed/chemical/Intercellular Adhesion Molecule-1,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1beta,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Thromboplastin,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/histone deacetylase 3
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0021-9258
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
28
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pubmed:volume |
282
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
28408-18
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:17675290-Acetylation,
pubmed-meshheading:17675290-Cells, Cultured,
pubmed-meshheading:17675290-E-Selectin,
pubmed-meshheading:17675290-Endothelial Cells,
pubmed-meshheading:17675290-Enzyme Induction,
pubmed-meshheading:17675290-Enzyme Inhibitors,
pubmed-meshheading:17675290-Histone Deacetylase Inhibitors,
pubmed-meshheading:17675290-Histone Deacetylases,
pubmed-meshheading:17675290-Histones,
pubmed-meshheading:17675290-Humans,
pubmed-meshheading:17675290-Intercellular Adhesion Molecule-1,
pubmed-meshheading:17675290-Interleukin-1beta,
pubmed-meshheading:17675290-Lipopolysaccharides,
pubmed-meshheading:17675290-Monocytes,
pubmed-meshheading:17675290-NF-kappa B,
pubmed-meshheading:17675290-Protein Binding,
pubmed-meshheading:17675290-RNA, Messenger,
pubmed-meshheading:17675290-RNA, Small Interfering,
pubmed-meshheading:17675290-Response Elements,
pubmed-meshheading:17675290-Thromboplastin,
pubmed-meshheading:17675290-Thrombosis,
pubmed-meshheading:17675290-Transcription, Genetic,
pubmed-meshheading:17675290-Tumor Necrosis Factor-alpha
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pubmed:year |
2007
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pubmed:articleTitle |
Histone deacetylase inhibitors suppress TF-kappaB-dependent agonist-driven tissue factor expression in endothelial cells and monocytes.
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pubmed:affiliation |
Medicine Department and Vascular Biology Center, University of Minnesota, Minnealpoles, Minnesota 55455, USA.
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pubmed:publicationType |
Journal Article,
Clinical Trial,
Research Support, N.I.H., Extramural
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