PT  - JOURNAL ARTICLE
AU  - Chi-Li Chung
AU  - Wei-Lin Chen
AU  - Yu-Wen Cheng
AU  - Yung-Chen Chou
AU  - Ming-Jen Hsu
AU  - Che-Jen Hsiao
AU  - Joen-Rong Sheu
AU  - George Hsiao
TI  - P66 Histone deacetylase inhibitor CBHA attenuates the expression of plasminogen activator inhibitor-1 in human pleural mesothelial cells
AID  - 10.1136/thx.2010.150979.17
DP  - 2010 Dec 01
TA  - Thorax
PG  - A105--A106
VI  - 65
IP  - Suppl 4
4099  - http://thorax.bmj.com/content/65/Suppl_4/A105.2.short
4100  - http://thorax.bmj.com/content/65/Suppl_4/A105.2.full
SO  - Thorax2010 Dec 01; 65
AB  - 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).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.