BET Inhibitor JQ1 Attenuates Atrial Fibrillation Through Modulation of Fibrosis, Calcium Homeostasis, and Mitochondrial Function in a Murine Model

Abstract

Bromodomain and extraterminal domain (BET) proteins act as epigenetic regulators of gene transcription. BET inhibitors have shown therapeutic potential in various models of heart failure; however, their efficacy in atrial fibrillation (AF) remains incompletely understood. This study investigated the effects of the BET inhibitor JQ1 in a mice model of AF. Wild-type male C57BL/6 mice were randomized into four groups: control, JQ1 alone (50 mg/kg, intraperitoneal), angiotensin II (AngII; 1 μg/kg/min), and AngII plus JQ1. After 2 weeks, electrophysiological studies revealed that JQ1 significantly reduced AngII-induced AF inducibility and duration. It also attenuated left atrial enlargement, diastolic dysfunction, and cardiac fibrosis. Molecular analyses indicated that JQ1 suppressed the AngII-induced upregulation of pro-fibrotic genes and restored Sirt1 expression. Moreover, JQ1 also inhibited AngII-enhanced oxidized CaMKII and phosphorylated RyR2 levels. In HL-1 atrial cardiomyocytes, JQ1 improved calcium handling abnormalities, shortened prolonged action potential duration (APD), and restored mitochondrial respiration and adenosine triphosphate (ATP) production, all of which had been impaired by AngII. These findings suggest that BET inhibition by JQ1 mitigates structural and electrical remodeling associated with AF by attenuating atrial fibrosis, and by restoring calcium homeostasis, mitochondrial function, and Sirt1 expression. JQ1 may represent a novel therapeutic strategy for the prevention and treatment of AF.