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Inhibition of bromodomain extraterminal histone readers alleviates skin fibrosis in experimental models of scleroderma
Sirapa Vichaikul, … , Amr H. Sawalha, Pei-Suen Tsou
Sirapa Vichaikul, … , Amr H. Sawalha, Pei-Suen Tsou
Published March 29, 2022
Citation Information: JCI Insight. 2022;7(9):e150871. https://doi.org/10.1172/jci.insight.150871.
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Research Article

Inhibition of bromodomain extraterminal histone readers alleviates skin fibrosis in experimental models of scleroderma

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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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Figure 7

BRD4 inhibitors show prominent antifibrotic effects in vitro and in vivo.

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BRD4 inhibitors show prominent antifibrotic effects in vitro and in vivo...
(A) Treating dcSSc fibroblasts with the specific BRD2 inhibitor BIC1 had minimal effect on cell proliferation, whereas inhibition of BRD4 using BRD4 inhibitors AZD5153 or ARV825 significantly reduced cell proliferation at concentrations of 1 and 10 μM. n = 5 patients. (B) Inhibition of BRD4 by ARV825 or AZD5153 in dcSSc fibroblasts significantly reduced both ACTA2 and COL1A1 expression, whereas blockade of BRD2 by BIC1 had no effect. n = 6 patients. (C) BRD4 inhibitors significantly decreased α-SMA (n = 7) and COL1 (n = 5) in dcSSc fibroblasts, whereas BRD2 inhibition by BIC1 had minimal effect on α-SMA (n = 6) but increased COL1 at 1 μM (n = 4 patients). (D) Bleomycin-treated mice had increased dermal thickness and hydroxyproline content in skin, and ARV825 or AZD5153 efficiently prevented skin fibrosis in these mice. Immunofluorescence staining of α-SMA–positive cells (green) is shown. Nuclei were stained with DAPI (blue). Original magnification, ×40–100. n = 9–10 mice. (E) BRD4 inhibitor AZD5153 significantly decreased intracellular Ca2+ and BRD2 inhibitor BIC1 significantly increased it. n = 6 patients. (F) Overexpression of CAMK2A resulted in significant increase in ACTA2 and COL1A1 expression and blocked the effect of AZD5153 on COL1A1 expression. n = 4 patients. (G) CAMK2A overexpression significantly increased cell proliferation while it abolished the effect of BRD4 inhibition on cell proliferation. n = 4 patients. Results are expressed as mean ± SD and P < 0.05 was considered significant. Significance was determined by 1-way ANOVA (A–D, F, and G), Kruskal-Wallis test (A–C), and Wilcoxon’s test (E). NT, no treatment.

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