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BRD4 as a therapeutic target for atrial fibrosis and atrial fibrillation.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2024 Aug 15; Vol. 977, pp. 176714. Date of Electronic Publication: 2024 Jun 06. - Publication Year :
- 2024
-
Abstract
- Objective: This study aimed to elucidate the molecular mechanisms by which BRD4 play a role in atrial fibrillation (AF).<br />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.<br />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.<br />Competing Interests: Declaration of competing interest None.<br /> (Copyright © 2024. Published by Elsevier B.V.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 977
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38849043
- Full Text :
- https://doi.org/10.1016/j.ejphar.2024.176714