P2X7 antagonism reduced atrial fibrillation susceptibility, improved conduction heterogeneity, and ameliorated structural and autonomic remodeling in vivo.
Does P2X7 inhibition reduce atrial fibrillation susceptibility and atrial remodeling in preclinical models?
The P2X7-ROS-MAPK signaling axis is a central mechanism in atrial fibrillation vulnerability, suggesting P2X7 inhibition as a potential therapeutic strategy.
Atrial fibrillation (AF), the most common clinical arrhythmia, is driven by inflammatory activation and oxidative stress, though precise molecular links remain unclear. This study identifies the P2X7 receptor as a key upstream regulator orchestrating proarrhythmic atrial remodeling through reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK) signaling. Transcriptomic analysis of rapid-paced cardiomyocytes revealed P2X7 upregulation and MAPK pathway enrichment. Functional validation demonstrated that P2X7 activation promotes ROS accumulation, MAPK phosphorylation (p-ERK, p-p38, and p-JNK), and pro-inflammatory cytokine release (IL-6 and IL-1β), culminating in action potential shortening and calcium handling dysfunction. Critically, both P2X7 inhibition (A-438079) and ROS scavenging (NAC) attenuated this signaling axis. In vivo, P2X7 antagonism reduced AF susceptibility, improved conduction heterogeneity, and ameliorated structural and autonomic remodeling. These results establish the P2X7-ROS-MAPK axis as a central mechanism in AF vulnerability and highlight its therapeutic potential.
Zhang et al. (2026) studied Atrial fibrillation. P2X7 inhibition (A-438079) and ROS scavenging (NAC) was evaluated on Atrial fibrillation susceptibility and atrial remodeling. P2X7 antagonism reduced atrial fibrillation susceptibility, improved conduction heterogeneity, and ameliorated structural and autonomic remodeling in vivo.
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