P2X7 receptor-mediated inflammatory and ionic remodeling promotes atrial fibrillation in diabetes

Diabetes mellitus (DM) is a major risk factor for atrial fibrillation (AF), yet the mechanisms by which diabetic metabolic stress promotes atrial arrhythmogenesis remain incompletely understood. Recent evidence suggests that purinergic signaling-driven sterile inflammation plays an important role in cardiac remodeling. This study aimed to investigate the role of the ATP-gated purinergic P2X7 receptor (P2X7R) in DM-associated AF and to explore its underlying mechanisms.

Rats were randomly assigned to four groups: control (Con), diabetes mellitus (DM), P2X7R overexpression in controls (Con+P2X7), and P2X7R knockdown in diabetic rats (DM + P2X7 KD), with gene manipulation achieved using AAV9-cTnT vectors. AF susceptibility, atrial structural and electrical remodeling were systematically evaluated using electrophysiological studies, optical mapping, patch-clamp recordings, and molecular analyses. DM markedly increased AF inducibility and duration, accompanied by enhanced sympathetic nerve activity and activation of P2X7R-related inflammatory signaling. Compared with controls, DM atria exhibited pronounced interstitial fibrosis, connexin remodeling, delayed atrial activation, slowed conduction velocity, and increased conduction heterogeneity. Atrial P2X7R overexpression in control rats recapitulated key arrhythmogenic features, whereas P2X7R KD in diabetic rats significantly attenuated atrial remodeling and reduced AF susceptibility, without altering the diabetes-induced increase in sympathetic activity. At the cellular level, P2X7R selectively modulated I_Na, I_Ca,L, and I_Kur while relatively preserving I_to, and was associated with mitochondrial dysfunction and disturbed Ca²⁺ homeostasis, characterized by increased mitochondrial reactive oxygen species, loss of mitochondrial membrane potential, increased cytosolic Ca²⁺ signals, and reduced mitochondrial Ca²⁺ uptake.

P2X7R-mediated inflammatory and mitochondrial signaling contribute to diabetic atrial remodeling and AF susceptibility. Targeting P2X7R may represent a potential therapeutic strategy for preventing AF in diabetes.