Bromodomain and extra-terminal (BET) proteins regulate antioxidant gene expression

Background : Oxidative stress, a key pathogenic factor in COPD, arises due to reactive oxygen species (ROS) accumulation and defective antioxidant defences in the lungs. The latter is partly due to acetylation of the antioxidant gene activator nuclear factor E2-related factor 2 (Nrf2). Bromodomain and extra-terminal (BET) proteins regulate gene transcription by binding to acetylated proteins and recruiting transcriptional regulators to gene promoters. Their role in antioxidant gene regulation is unknown. Aims & Objectives: Determine the role of BET proteins in antioxidant gene expression in human primary airway smooth muscle cells (ASMCs) and THP1 monocytic cells. Methods: BET proteins were inhibited using the selective inhibitor (+) - JQ1 [JQ1]. mRNA and protein expression was determined by real-time PCR and western blotting, respectively. Results: In ASMCs, JQ1 (50-1000nM) increased the mRNA of Nrf2-mediated antioxidants haem oxygenase (HO)-1 (∼5-fold; p Conclusions: BET proteins may augment antioxidant defences and prevent oxidative stress in addition to their known anti-inflammatory and anti-proliferative actions. They have potential as novel therapeutic targets in COPD.