Bromodomain and Extraterminal (BET) Protein Inhibition Restores Redox Balance and Inhibits Myofibroblast Activation.
Carmel J W StockCharalambos MichaeloudesPatricia LeoniAndrew L DurhamSharon MumbyAthol U WellsKian Fan ChungIssssswan M AdcockElisabetta A RenzoniGisela E LindahlPublished in: BioMed research international (2019)
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.
Keyphrases
- transforming growth factor
- reactive oxygen species
- poor prognosis
- epithelial mesenchymal transition
- amyotrophic lateral sclerosis
- high glucose
- binding protein
- pulmonary fibrosis
- idiopathic pulmonary fibrosis
- diabetic rats
- oxidative stress
- drug induced
- dna methylation
- long non coding rna
- endothelial cells
- systemic sclerosis
- transcription factor
- climate change
- big data
- machine learning
- single cell
- human health
- protein protein