Histone deacetylase 7 mediates endothelin-1-induced connective tissue growth factor expression in human lung fibroblasts through p300 and activator protein-1 activation

Abstract

Background Histone deacetylase (HDAC) inhibition was reported to ameliorate lung fibrosis in animal models. However, little is known about the underlying mechanism of HDAC7 in the regulation of CTGF production in lung fibroblasts. Methods The role of HDAC7 in CTGF production caused by ET-1 stimulation in WI-38 cells (human lung fibroblast) was examined. We also evaluated the expression of HDAC7 in the lung of ovalbumin-induced airway fibrosis model. Statistical data were shown as mean ± standard error. Results ET-1-stimulated CTGF and α-SMA expression was attenuated by small interfering (si)RNA interference of HDAC7. ET-1 promoted HDAC7 translocation from the cytosol to nucleus. ET-1-stimulated CTGF expression was reduced by the transfection of p300 siRNA. ET-1 induced an increase in p300 activity. Furthermore, the acetylation of c-Jun was time-dependently induced by ET-1 stimulation, which was reduced by transfection of either HDAC7 or p300 siRNA. Both transfection of HDAC7 and p300 siRNA suppressed the ET-1-increased activity of AP-1-luciferase. Moreover, the presence of HDAC7 was required for ET-1-stimulated formation of HDAC7, p300, and AP-1 complex and recruitment to the CTGF promoter region. In an ovalbumin-induced airway fibrosis model, the protein level of HDAC7 was increased in the lung tissue, and the distribution of HDAC7 was colocalized with α-SMA-positive cells in the subepithelial layer of the airway. Conclusions ET-1 activates HDAC7 to initiate AP-1 transcriptional activity by recruiting p300 and eventually promotes the production of CTGF. HDAC7 might play a vital role in airway fibrosis and have the potential to be developed as a therapeutic target.

State of the Art in Idiopathic Pulmonary Fibrosis

“…In detail, endothelin-1 promoted HDAC7 translocation from the cytosol to nucleus and HDAC7 initiated AP-1 transcriptional activity (surprisingly) through the recruitment of p300 and consequent p300-mediated AP-1 acetylation. Conversely, RNAi-mediated silencing of either HDAC7 or EP300 suppressed endothelin-1-induced CTGF expression [296]. Taken together, these results indicate a crucial role for HDAC7 in cytokine/growth factor-induced expression of profibrotic molecules during fibrogenesis.…”

Endothelin-1 induces connective tissue growth factor expression in human lung fibroblasts by disrupting HDAC2/Sin3A/MeCP2 corepressor complex

“…CTGF expression is regulated through the epigenetic modification of DNA, such as histone acetylation [ 12 ]. In our previous study, HDAC7 regulated ET-1-induced CTGF expression through the activation of AP-1 in WI-38 cells [ 22 ]. In this study, we evaluated the role of HDAC2 and HDAC7 in ET-1-induced histone H3 acetylation.…”

“…Our previous study indicated that ET-1 stimulates the expression of CTGF through the ET A R/JNK/AP-1 signaling pathway and that CTGF is required for ET-1-stimulated myofibroblast differentiation [ 53 ]. Moreover, ET-1 activates p300 and HDAC7 to initiate AP-1 transcriptional activity and eventually promotes the expression of CTGF [ 22 ]. In this study, we found that ET-1 increased HDAC2 phosphorylation through MAPKs and then induced the dissociation of the HDAC2/Sin3A/MeCP2 corepressor complex from the CTGF promoter region, which in turn promoted histone H3 acetylation, thus increasing CTGF expression.…”

“…Elevated expression of ET-1 by the bronchial epithelium is associated with airflow obstruction and airway remodeling, and it is often observed in severe refractory asthma [ 42 ]. In our previous studies, we have observed the following: first, the ET A receptor (ET A R)-dependent pathway mediates CTGF expression, which prompts fibrocyte differentiation into myofibroblasts in chronic obstructive asthma [ 52 ]; second, ET-1 stimulates CTGF production through c-Jun N-terminal kinase (JNK)/activator protein (AP)-1 activation in lung fibroblasts [ 53 ]; third, ET-1 activates HDAC7 and p300, thereby leading to the initiation of AP-1 transcriptional activity and eventually the promotion of CTGF production in lung fibroblasts [ 22 ].…”

Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis

“…Moreover, sodium butyrate (NaBu) significantly attenuates Ang-II-induced cardiac hypertrophy and fibrosis, and inflammation by inhibiting the activation of the COX2/PGE 2 pathway in HDAC5/HDAC6-dependent manner [ 69 ]. The other members of Class II HDACs have been sparsely studied in cardiac fibrosis, but have been discovered to be associated with other organ fibrosis models [ 85 , 86 , 87 , 88 ].…”