1. BRD4 as a therapeutic target for atrial fibrosis and atrial fibrillation.
- Author
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Song S, Yuan J, Fang G, Li Y, Ding S, Wang Y, and Wang Q
- Subjects
- Animals, Humans, Mice, Male, Fibroblasts drug effects, Fibroblasts metabolism, Fibroblasts pathology, Cell Proliferation drug effects, Nuclear Proteins genetics, Nuclear Proteins metabolism, Nuclear Proteins antagonists & inhibitors, Disease Models, Animal, Mice, Inbred C57BL, Angiotensin II pharmacology, Extracellular Matrix metabolism, Extracellular Matrix drug effects, Molecular Targeted Therapy, Bromodomain Containing Proteins, Atrial Fibrillation genetics, Atrial Fibrillation metabolism, Atrial Fibrillation pathology, Atrial Fibrillation drug therapy, Fibrosis, Transcription Factors genetics, Transcription Factors antagonists & inhibitors, Transcription Factors metabolism, Heart Atria pathology, Heart Atria drug effects, Heart Atria metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins metabolism, Mice, Knockout, Azepines pharmacology, Azepines therapeutic use, Triazoles pharmacology, Triazoles therapeutic use
- Abstract
Objective: This study aimed to elucidate the molecular mechanisms by which BRD4 play a role in atrial fibrillation (AF)., Methods and Results: We used a discovery-driven approach to detect BRD4 expression in the atria of patients with AF and in various murine models of atrial fibrosis. We used a BRD4 inhibitor (JQ1) and atrial fibroblast (aFB)-specific BRD4-knockout mice to elucidate the role of BRD4 in AF. We further examined the underlying mechanisms using RNA-seq and ChIP-seq analyses in vitro, to identify key downstream targets of BRD4. We found that BRD4 expression is significantly increased in patients with AF, with accompanying atrial fibrosis and aFB differentiation. We showed that JQ1 treatment and shRNA-based molecular silencing of BRD4 blocked ANG-II-induced extracellular matrix production and cell-cycle progression in aFBs. BRD4-related RNA-seq and ChIP-seq analyses in aFBs demonstrated enrichment of a subset of promoters related to the expression of profibrotic and proliferation-related genes. The pharmacological inhibition of BRD4 in vivo or in aFB-specific BRD4-knockout in mice limited ANG-II-induced atrial fibrosis, atrial enlargement, and AF susceptibility., Conclusion: Our findings suggest that BRD4 plays a key role in pathological AF, at least partially by activating aFB proliferation and ECM synthesis. This study provides mechanistic insights into the development of BRD4 inhibitors as targeted antiarrhythmic therapies., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
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