Sotagliflozin attenuates atrial oxidative stress and the susceptibility to atrial fibrillation by activating the NRF2/HO-1 pathway

Background: Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia. Sotagliflozin (Sota), an SGLT1/2 inhibitor, has demonstrated potential cardiovascular protective effects, but its role and underlying mechanisms in AF remain unclear. This study aims to investigate the effects of Sota on AF and explore the underlying mechanisms.

Methods: Establishing an AF model by injecting acetylcholine/calcium chloride (Ach/CaCl2) through the tail vein of mice. Mice were randomly assigned to four groups: Control, Sota, AF model, and AF model + Sota. Atrial structural changes, electrophysiological remodeling, oxidative stress levels, and inflammatory biomarkers were evaluated. Additionally, potential signaling pathways affected by Sota were examined, with relevant signaling molecules analyzed.

Results: Sota treatment significantly reduced AF susceptibility in the Ach/CaCl2-induced AF model, improving atrial remodeling. Sota notably diminished the oxidative stress induced by AF in the atria, reduced pro-inflammatory factors, and restored mitochondrial morphology and function. Confocal microscopy and Western blot (WB) analyses confirmed that Sota promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and activated the NRF2/HO-1 pathway. Furthermore, the NRF2 inhibitor ML385 significantly reversed Sota's antioxidant effects and abolished its protective effects on atrial.

Conclusions: Sota alleviates atrial oxidative stress, improves atrial remodeling, and significantly reduces susceptibility to AF by activating the NRF2/HO-1 pathway. These findings offer new insights into the potential therapeutic application of Sota in the treatment of AF.

Atrial fibrillation; NRF2; Oxidative stress; Sotagliflozin.