Dapagliflozin attenuates cardiac remodeling and dysfunction in rats with β-adrenergic receptor overactivation through restoring calcium handling and suppressing cardiomyocyte apoptosis

Background: Long-term β-adrenergic receptor (β-AR) activation can impair myocardial structure and function. Dapagliflozin (DAPA) has been reported to improve clinical prognosis in heart failure patients, whereas the exact mechanism remains unclear. Here, we investigated the effects of DAPA against β-AR overactivation toxicity and explored the underlying mechanism. Methods and Results: Rats were randomized to receive saline + placebo, isoproterenol (ISO, 5 mg/kg/day, intraperitoneally) + placebo, or ISO + DAPA (1 mg/kg/day, intragastrically) for 2-week. DAPA treatment improved cardiac function, alleviated myocardial fibrosis, prevented cardiomyocytes (CMs) apoptosis, and decreased the expression of ER stress-mediated apoptosis markers in ISO-treated hearts. In isolated CMs, 2-week ISO stimulation resulted in deteriorated kinetics of cellular contraction and relaxation, increased diastolic intracellular Ca(2+) level and decay time constant of Ca(2+) transient (CaT) but decreased CaT amplitude and sarcoplasmic reticulum (SR) Ca(2+) level. However, DAPA treatment prevented abnormal Ca(2+) handling and contractile dysfunction in CMs from ISO-treated hearts. Consistently, DAPA treatment upregulated the expression of SR Ca(2+)-ATPase protein and ryanodine receptor 2 (RyR2) but reduced the expression of phosphorylated-RyR2, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), and phosphorylated-CaMKII in ventricles from ISO-treated rats. Conclusion: DAPA prevented myocardial remodeling and cardiac dysfunction in rats with β-AR overactivation via restoring calcium handling and suppressing ER stress-related CMs apoptosis.