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Citation Information: JCI Insight. 2022;7(9):e150871. https://doi.org/10.1172/jci.insight.150871.
Abstract
Binding of the bromodomain and extraterminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. We sought to determine the antifibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan-BET inhibitor, JQ1; BRD2 inhibitor, BIC1; or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed antifibrotic effects in an animal model of SSc and in patient-derived diffuse cutaneous SSc (dcSSc) fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium (Ca2+) signaling. The antifibrotic effect of BRD4 inhibition was mediated at least in part by downregulation of Ca2+/calmodulin–dependent protein kinase II α and reduction of intracellular Ca2+ concentrations. On the basis of these results, we propose targeting Ca2+ pathways or BRD4 as potentially novel therapeutic approaches for progressive tissue fibrosis.
Authors
Sirapa Vichaikul, Mikel Gurrea-Rubio, M. Asif Amin, Phillip L. Campbell, Qi Wu, Megan N. Mattichak, William D. Brodie, Pamela J. Palisoc, Mustafa Ali, Sei Muraoka, Jeffrey H. Ruth, Ellen N. Model, Dallas M. Rohraff, Jonatan L. Hervoso, Yang Mao-Draayer, David A. Fox, Dinesh Khanna, Amr H. Sawalha, Pei-Suen Tsou
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