Background Plasminogen activator inhibitor-1 (PAI-1), primarily up-regulated by transforming growth factor (TGF)-β, is essential for development of fibrosis. Histone deacetylases (HDACs) have been shown to modulate gene expression and fibrogenesis in various tissues. However, the implications of HDAC in PAI-1 expression and pleural fibrosis remain unclear. We examined the effects of m-carboxycinnamic acid bis-hydroxamide (CBHA), a hybrid-polar HDAC inhibitor, on PAI-1 expression in a human pleural mesothelial cell line (MeT-5A).Methods MeT-5A cells were treated with TGF-β1 (10 ng/ml) in the presence or absence of CBHA (0.2–1 μM). The expression and stability of PAI-1 mRNA and protein, PAI-1 promoter activity, activation of Smad signaling, and protein–protein interactions of Smads with transcriptional cofactors Sp1 and coactivator p300 were assayed using the methods of Western blotting, reverse transcription-polymerase chain reaction, transient transfection and luciferase activity assay, immunoflurescence staining and immunoprecipitation, respectively.Results CBHA significantly inhibited TGF-β1-induced PAI-1 mRNA and protein expression, and attenuated PAI-1 promoter activity in MeT-5A cells. CBHA abrogated TGF-β1-induced Smad4 nuclear translocation, but not Smad2/3 activation. Furthermore, the TGF-β1-induced association of Smad4 with p300, but not with Sp1, was disrupted by CBHA. Alternatively, CBHA accelerated PAI-1 mRNA degradation, possibly through suppression of the mRNA stabilizing protein nucleolin (Abstract P66 Figure 1).Conclusion Our data suggests that inhibition of HDAC activity by CBHA may attenuate TGF-β1-induced PAI-1 expression in human pleural mesothelial cells through modulation of cellular signaling at multiple levels. HDAC inhibitors may be employed as potential therapeutic agents for pleural fibrosis.
Original languageEnglish
Number of pages2
Publication statusPublished - 2010
EventBritish Thoracic Society Winter Meeting 2010 - The Queen Elizabeth II Conference Centre, London, United Kingdom
Duration: Dec 1 2010Dec 3 2010


ConferenceBritish Thoracic Society Winter Meeting 2010
Country/TerritoryUnited Kingdom


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