Dapagliflozin attenuates the vulnerability to atrial fibrillation in rats with lipopolysaccharide-induced myocardial injury

Oxidative stress is an essential component participating in the development and maintenance of atrial fibrillation (AF). Dapagliflozin, a SGLT2 inhibitor, has been shown to exert cardioprotective effects by ameliorating oxidative stress in multiple heart disease models. However, its potential to attenuate lipopolysaccharide (LPS)-induced myocardial injury in rats remains unknown. This study aims to investigate the role of dapagliflozin in LPS-induced myocardial injury and the potential mechanisms involved. Rats were intraperitoneally administered LPS to induce sepsis-like condition. The intervention was conducted with intraperitoneal injection of dapagliflozin or saline 1 h in advance. The effects of dapagliflozin were detected by electrophysiological recordings, western blot, qPCR, ELISA, HE staining, immunohistochemistry and fluorescence. We further validated the mechanism in vitro using HL-1 cells. Dapagliflozin significantly improved LPS-induced myocardial injury, reduced susceptibility to AF, and mitigated atrial tissue inflammatory cell infiltration and atrial myocyte apoptosis. These were correlated with the Nrf2/HO-1 signaling pathway, which subsequently reduced oxidative stress. Subsequently, we used a specific inhibitor of the Nrf2/HO-1 pathway in vitro, reversed the anti-oxidative stress effects of dapagliflozin on HL-1 cells, further confirming the Nrf2/HO-1 pathway’s pivotal role in dapagliflozin-mediated cardioprotection. Dapagliflozin ameliorated myocardial injury and susceptibility to AF induced by LPS through anti-oxidative stress, which relied on upregulation of the Nrf2/HO-1 pathway.