1. A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signalling.
- Author
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Liu Y, Wang Z, Wang J, Lam W, Kwong S, Li F, Friedman SL, Zhou S, Ren Q, Xu Z, Wang X, Ji L, Tang S, Zhang H, Lui EL, and Ye T
- Subjects
- Acetylation, Animals, Apoptosis drug effects, Carbon Tetrachloride, Cell Line, Dose-Response Relationship, Drug, Hepatic Stellate Cells drug effects, Hepatic Stellate Cells enzymology, Hepatic Stellate Cells pathology, Histone Deacetylases genetics, Histones metabolism, Humans, Liver blood supply, Liver enzymology, Liver pathology, Liver Cirrhosis, Experimental chemically induced, Liver Cirrhosis, Experimental enzymology, Liver Cirrhosis, Experimental pathology, Male, Mice, Mice, Inbred BALB C, RNA Interference, Rats, Time Factors, Transfection, Angiogenesis Inhibitors pharmacology, Depsipeptides pharmacology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Liver drug effects, Liver Cirrhosis, Experimental prevention & control, Neovascularization, Physiologic drug effects, Signal Transduction drug effects, Thiazoles pharmacology, Transforming Growth Factor beta metabolism, Vascular Endothelial Growth Factor A metabolism
- Abstract
Background & Aims: Largazole is a novel histone deacetylase (HDAC) inhibitor. This study investigated the effects of largazole against liver fibrosis., Methods: The in vitro effects of largazole were examined using hepatic stellate cells (HSCs). In vivo effects of largazole were studied using a mouse liver fibrotic model induced by CCl4 ., Results: Largazole augmented acetylation of histone H3 (H3) and histone H4 (H4) in HSCs. It directly inhibited the activation of HSCs owing to HDAC inhibitory activity as the antifibrotic effect of largazole was significantly decreased in cells with HDAC1, HDAC2 and HDAC3 knockdown. Largazole also induced apoptosis of HSCs. Largazole not only inhibited the expression of TGFβR2, but also reduced phosphorylation of Smad2 and Akt induced by TGF-β1. Largazole also inhibited the expression of vascular endothelial growth factor (VEGF) and its receptor. VEGF-induced proliferation of HSCs and activation of Akt and p38MAPK were also suppressed by largazole. In vivo, largazole reduced the expression of collagen I, α-smooth muscle actin and tissue inhibitor of metalloproteinase-1 in CCl4 -induced fibrosis, and these antifibrotic effects were associated with increased acetylation of H3 and H4. Largazole also induced HSCs to undergo apoptosis in vivo, which was correlated with downregulation of bcl-2 and bcl-xL. Furthermore, largazole inhibited angiogenesis in vivo as evidenced by reduced expression of CD34, VEGF and VEGFR. In addition to its antifibrotic activity, the drug reduced inflammatory activity in CCl4 -induced liver fibrosis., Conclusions: Our findings revealed a novel role of largazole in the treatment of liver fibrosis. Through multiple mechanisms, largazole could be a potentially effective antifibrotic agent., (© 2012 John Wiley & Sons A/S.)
- Published
- 2013
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