P66 Histone deacetylase inhibitor CBHA attenuates the expression of plasminogen activator inhibitor-1 in human pleural mesothelial cells. (16th November 2010)

• Record Type: Journal Article
• Authors: Chung, Chi-Li; Chen, Wei-Lin; Cheng, Yu-Wen; Chou, Yung-Chen; Hsu, Ming-Jen; Hsiao, Che-Jen; Sheu, Joen-Rong; Hsiao, George
• Is Part Of: Thorax. Volume 65(2010)Supplement 4
• Page Start: A105
• Page End: A106
• Publication Date: 2010-11-16
• Subjects: Chest -- Diseases -- Periodicals; Thorax; Chest -- Diseases; Periodicals; Periodicals; 617.54
• DOI: 10.1136/thx.2010.150979.17
• Languages: English
• ISSNs: 0040-6376

Abstract

Abstract : 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.