High-altitude hypoxia promotes BRD4-mediated activation of the Wnt/ β-catenin pathway and disruption of intestinal barrier

Cell Signal. 2024 Apr 20:111187. doi: 10.1016/j.cellsig.2024.111187. Online ahead of print.ABSTRACTHypobaric hypoxia, commonly experienced at elevated altitudes, presents significant physiological challenges. Our investigation is centered on the impact of the bromodomain protein 4 (BRD4) under these conditions, especially its interaction with the Wnt/β-Catenin pathway and resultant effects on glycolytic inflammation and intestinal barrier stability. By combining transcriptome sequencing with bioinformatics, we identified BRD4's key role in hypoxia-related intestinal anomalies. Clinical parameters of altitude sickness patients, including serum BRD4 levels, inflammatory markers, and barrier integrity metrics, were scrutinized. In vitro studies using CCD 841 CoN cells depicted expression changes in BRD4, Interleukin (IL)-1β, IL-6, and β-Catenin. Transepithelial electrical resistance (TEER) and FD4 analyses assessed barrier resilience. Hypoxia-induced mouse models, analyzed via H&E staining and Western blot, provided insights into barrier and protein alterations. Under hypoxic conditions, marked BRD4 expression variations emerged. Elevated serum BRD4 in patients coincided with intensified Wnt signaling, inflammation, and barrier deterioration. In vitro, findings showed hypoxia-induced upregulation of BRD4 and inflammatory markers but a decline in Occludin and ZO1, affecting barrier strength-effects mitigated by BRD4 inhibition. Mouse models echoed these patterns, linking B...

Source: Cellular Signalling - April 22, 2024 Category: Cytology Authors: Yun-Han Yang Fang Yan Wenqiang Yuan Peng-Shuang Shi Shi-Min Wu De-Jun Cui Source Type: research