Research article summary (published 29 Jun 2001):

Trichostatin A, lead compound for development of antifibrogenic drugs.

Full Abstract

Eukaryotic gene expression has mainly been studied in the context of trans-acting transcription factors and their interaction with regulatory cis-elements. Evidence is accumulating, that the higher order structure of chromatin also plays an essential role in eukaryotic gene expression. Hepatic stellate cells are the major cellular source of extracellular matrix synthesis in chronic liver diseases leading to fibrosis. We explored the antifibrogenic effect of the histone deacetylase inhibitor trichostatin A (TSA) on hepatic stellate cells in vitro. Primary hepatic stellate cells as well as activated, subcultured stellate cells were exposed to 10(-7) M-10(-9) M TSA. Collagens type I and III, and smooth muscle alpha-actin (alpha-SMA), a marker for transdifferentiation, were investigated at the protein and mRNA level by performing Northern hybridisation and quantitative immunoprecipitation. The antiproliferative effect was examined by 3H-thymidine incorporation and cell counting. Hyperacetylation of histone H4 was demonstrated by acid urea Triton-X-100 (AUT) polyacrylamide gel electrophoresis. TSA at 10(-7) M retarded the morphological changes characteristics for activation of primary stellate cells. Synthesis of collagens type I and III, and alpha-SMA was strongly inhibited at both protein and mRNA level. The proliferation rate of primary hepatic stellate cells was strongly suppressed by 10(-7) M TSA. Hyperacetylation of histone H4 showed to be maximal at 10(-7) M TSA. Primary hepatic stellate cells were more affected by TSA than subcultured stellate cells.

Author information

Author/s: Rombouts, K (K); Niki, T (T); Wielant, A (A); Hellemans, K (K); Geerts, A (A);

Affiliation: Laboratory for Molecular Liver Cell Biology, Free University of Brussels (VUB), Laarbeeklaan 103, 1090 Brussels-Jette, Belgium. krom(-atsign-)cyto.vub.ac.be

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Acta gastro-enterologica Belgica (Acta Gastroenterol Belg), published in Belgium. (Language: eng)

Reference: -2001 Jul-Sep; vol 64 (issue 3) : pp 239-46

Dates: Created 2001/10/26; Completed 2001/12/05; Revised 2006/11/15;

PMID: 11680040, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Cell Differentiation - drug effects Collagen Type I - biosynthesis; drug effects Collagen Type III - biosynthesis; drug effects Enzyme Inhibitors - pharmacology Fibroblasts - drug effects; metabolism Fibrosis - prevention & control Histone Deacetylases - antagonists & inhibitors Histones - drug effects Hydroxamic Acids - antagonists & inhibitors; pharmacology

Hydroxamic Acids - antagonists & inhibitors; pharmacology Immunohistochemistry Liver - drug effects; metabolism; pathology Male Models, Animal Muscle, Smooth - cytology; drug effects; metabolism Procollagen - biosynthesis; drug effects RNA, Messenger - biosynthesis; drug effects Rats Rats, Wistar

Associated Chemicals: Collagen Type I (0) ; Collagen Type III (0) ; Enzyme Inhibitors (0) ; Histones (0) ; Hydroxamic Acids (0) ; Procollagen (0) ; RNA, Messenger (0) ; trichostatin A (58880-19-6) ; Histone Deacetylases (EC 3.5.1.-)

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