Dapagliflozin attenuates arrhythmic vulnerabilities by regulating connexin43 expression via the AMPK pathway in post-infarcted rat hearts

We have demonstrated that dapagliflozin, a sodium-glucose cotransporter (SGLT) 2 inhibitor, attenuates reactive oxygen species (ROS) production. Connexin43 playing a role in ventricular arrhythmia is sensitive to redox status. No data are available on the effects of dapagliflozin on arrhythmogenesis. This study was to determine whether dapagliflozin attenuated arrhythmias through modulating AMP-activated protein kinase (AMPK)/free radicals-induced connexin43 after myocardial infarction. After coronary ligation, normoglycemic male Wistar rats were randomized to either vehicle or dapagliflozin (0.1 mg/kg per day) for 4 weeks. Myocardial ROS levels were significantly increased (p < 0.05) and connexin43 levels were substantially decreased after myocardial infarction (p < 0.05). Dapagliflozin administration was associated with increased SGLT1, attenuated ROS and increased connexin43 levels in myocardium (all p < 0.05). During programmed electrical stimulation, arrhythmic severity was significantly improved in the dapagliflozin-treated infarcted rats than those in the vehicle-treated infarcted rats (p < 0.05). Dapagliflozin significantly increased AMPK phosphorylation compared to vehicle after infarction (p < 0.05). Inhibition of AMPK signaling by SBI-0206965 prevented increased SGLT1 and blocked the effects of dapagliflozin on attenuated ROS levels and increased connexin43 phosphorylation (all p < 0.05). SGLT1 inhibited by KGA-2727 showed attenuated ROS levels and increased connexin43 phosphorylation (both p < 0.05) although AMPK phosphorylation was not changed, implying SGLT1 activation was mediated by AMPK in dapagliflozin-treated hearts. Dapagliflozin-treated hearts had significantly increased connexin43 phosphorylation (p < 0.05), which was significantly decreased after adding 3-morpholinosydnonimine (p < 0.05). These data indicate that clinically-relevant dapagliflozin concentrations decreased free radicals content and increased connexin43 levels through AMPK-dependent and SGLT1-independent mechanisms, which attenuated ventricular arrhythmias in the normoglycemic infarcted rats.