Suppression of bromodomain-containing protein 4 protects trophoblast cells from oxidative stress injury by enhancing Nrf2 activation.

Abstract

Oxidative stress is considered a key hallmark of preeclampsia, which causes the dysregulation of trophoblast cells, and it contributes to the pathogenesis of preeclampsia. Emerging evidence has suggested bromodomain-containing protein 4 (BRD4) as a key regulator of oxidative stress in multiple cell types. However, whether BRD4 participates in regulating oxidative stress in trophoblast cells remains undetermined. The current study was designed to explore the potential function of BRD4 in the regulation of oxidative stress in trophoblast cells. Our data revealed that BRD4 expression was elevated in trophoblast cells stimulated with hydrogen peroxide. Exposure to hydrogen peroxide caused marked decreases in the levels of proliferation and invasion but promoted apoptosis and the production of ROS in trophoblast cells. Knockdown of BRD4, or treatment with a BRD4 inhibitor, markedly increased the levels of cell proliferation and invasion and decreased apoptosis and ROS production following the hydrogen peroxide challenge. Further data indicated that suppression of BRD4 markedly decreased the expression levels of Keap1, but increased the nuclear expression of Nrf2 and enhanced Nrf2-mediated transcriptional activity. BRD4 inhibition-mediated protective effects were markedly reversed by Keap1 overexpression or Nrf2 inhibition. Overall, these results demonstrated that BRD4 inhibition attenuated hydrogen peroxide-induced oxidative stress injury in trophoblast cells by enhancing Nrf2 activation via the downregulation of Keap1. Our study highlights the potential importance of the BRD4/Keap1/Nrf2 axis in the modulation of the oxidative stress response in trophoblast cells. Targeted inhibition of BRD4 may offer new opportunities for the development of innovative therapeutic approaches to treat preeclampsia.