Imperial College London
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DrCharalambosMichaeloudes

Faculty of Medicine, National Heart & Lung Institute

Honorary Research Fellow
 
 
 
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Contact

 

c.michaeloudes04

 
 
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Location

 

223Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Stock:2019:2019/1484736,
author = {Stock, CJW and Michaeloudes, C and Leoni, P and Durham, AL and Mumby, S and Wells, AU and Chung, KF and Adcock, IM and Renzoni, E and Lindahl, GE},
doi = {2019/1484736},
journal = {BioMed Research International},
title = {Bromodomain and extra-terminal (BET) protein inhibition restores redox balance and inhibits myofibroblast activation},
url = {http://dx.doi.org/10.1155/2019/1484736},
volume = {2019},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background and Objective. Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor-β (TGF-β) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts. Methods. In TGF-β-stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by α-smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation. Results and Conclusions. Affymetrix gene array analysis revealed increased NOX4 and reduced SOD2 expression in SSc and IPF fibroblasts. SOD2 silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF-β increased NOX4 and inhibited SOD2 expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF-β-mediated NOX4/SOD2 imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the NOX4 promoter and drive TGF-β-induced NOX4 expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.
AU  - Stock,CJW
AU  - Michaeloudes,C
AU  - Leoni,P
AU  - Durham,AL
AU  - Mumby,S
AU  - Wells,AU
AU  - Chung,KF
AU  - Adcock,IM
AU  - Renzoni,E
AU  - Lindahl,GE
DO  - 2019/1484736
PY  - 2019///
SN  - 2314-6133
TI  - Bromodomain and extra-terminal (BET) protein inhibition restores redox balance and inhibits myofibroblast activation
T2  - BioMed Research International
UR  - http://dx.doi.org/10.1155/2019/1484736
UR  - http://hdl.handle.net/10044/1/70029
VL  - 2019
ER  -
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