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Increased apoptosis in fibrotic lung fibroblasts under the effects of histone deacetylase inhibitor SAHA

Idiopathic pulmonary fibrosis (IPF) is a complex and deadly disease with no clear etiology and no effective therapy. Epigenetic regulation, including DNA methylation and histone modifications, may play a role in the pathogenesis of IPF. Histone deacetylase (HDAC) inhibitors are promising anti‐cancer agents, have anti‐fibrotic effects, suberoylanilide hydroxamic acid (SAHA) is one of them. In this study, we examined if SAHA can affect the survival of apoptosis‐resistant fibrotic lung fibroblasts. The cells were exposed to SAHA for 60h before Annexin‐V FITC apoptosis analysis. About 60% of the SAHA treated fibrotic fibroblasts underwent apoptosis compared to about only 6% in the control group. Immunoblots of fibrotic lung fibroblasts treated with the HDAC inhibitor showed down‐regulation of the p‐ERK survival pathway, and decreased expression of α‐smooth muscle actin. Real‐time RT‐PCR showed the up‐regulation of pro‐apoptotic gene BAK, while down‐regulation of the anti‐apoptotic gene (Bcl‐2) in SAHA treated fibrotic fibroblasts. Our data indicate that SAHA can induce fibrotic lung fibroblasts apoptosis, affect the survival pathway and the expression of important apoptotic‐related genes. Future studies will explore mechanisms by which HDAC inhibitor affects apoptosis. Understanding these molecular mechanisms may uncover novel therapeutic targets for this deadly disease.