Department of Obstetrics, Northwest Women's and Children's Hospital, Xi'an, Shaanxi, China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of 117799Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Hum Exp Toxicol. 2021 May;40(5):742-753. doi: 10.1177/0960327120968857. Epub 2020 Oct 23.
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.
氧化应激被认为是子痫前期的一个关键标志，它导致滋养细胞的失调，并有助于子痫前期的发病机制。新出现的证据表明溴结构域蛋白 4（BRD4）是多种细胞类型中氧化应激的关键调节剂。然而，BRD4 是否参与调节滋养细胞中的氧化应激仍未确定。本研究旨在探讨 BRD4 在调节滋养细胞氧化应激中的潜在功能。我们的数据显示，BRD4 在过氧化氢刺激的滋养细胞中表达上调。过氧化氢暴露导致滋养细胞的增殖和侵袭水平显著降低，但促进了细胞凋亡和 ROS 的产生。BRD4 的敲低或 BRD4 抑制剂的处理显著增加了过氧化氢处理后细胞的增殖和侵袭水平，同时降低了细胞凋亡和 ROS 的产生。进一步的数据表明，抑制 BRD4 显著降低了 Keap1 的表达水平，但增加了 Nrf2 的核表达并增强了 Nrf2 介导的转录活性。Keap1 过表达或 Nrf2 抑制显著逆转了 BRD4 抑制介导的保护作用。总的来说，这些结果表明 BRD4 抑制通过下调 Keap1 增强 Nrf2 激活来减轻过氧化氢诱导的滋养细胞氧化应激损伤。我们的研究强调了 BRD4/Keap1/Nrf2 轴在调节滋养细胞氧化应激反应中的潜在重要性。靶向抑制 BRD4 可能为开发治疗子痫前期的创新治疗方法提供新的机会。
