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 Ca2+ level and decay time constant of Ca2+ transient (CaT) but decreased CaT amplitude and sarcoplasmic reticulum (SR) Ca2+ level. However, DAPA treatment prevented abnormal Ca2+ handling and contractile dysfunction in CMs from ISO-treated hearts. Consistently, DAPA treatment upregulated the expression of SR Ca2+-ATPase protein and ryanodine receptor 2 (RyR2) but reduced the expression of phosphorylated-RyR2, Ca2+/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.

中文翻译：

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Dapagliflozin 通过恢复钙处理和抑制心肌细胞凋亡来减轻 β-肾上腺素能受体过度激活大鼠的心脏重塑和功能障碍。

背景：长期β-肾上腺素能受体（β-AR）激活会损害心肌结构和功能。据报道，达格列净（DAPA）可改善心力衰竭患者的临床预后，但确切机制尚不清楚。在这里，我们研究了 DAPA 对 β-AR 过度激活毒性的影响，并探讨了其潜在机制。 方法和结果：大鼠被随机分配接受盐水 + 安慰剂、异丙肾上腺素（ISO，5 mg/kg/天，腹腔注射）+ 安慰剂，或ISO + DAPA（1 mg/kg/天，灌胃），持续 2 周。在 ISO 处理的心脏中，DAPA 治疗可改善心脏功能，减轻心肌纤维化，防止心肌细胞 (CM) 凋亡，并降低 ER 应激介导的凋亡标记物的表达。在孤立的 CM 中，2 周的 ISO 刺激导致细胞收缩和舒张动力学恶化、舒张期细胞内 Ca2+ 水平和 Ca2+ 瞬变 (CaT) 衰减时间常数增加，但降低了 CaT 幅度和肌浆网 (SR) Ca2+ 水平。然而，DAPA 治疗可防止 ISO 处理心脏的 CM 中异常的 Ca2+ 处理和收缩功能障碍。一致地，DAPA处理上调了ISO-心室中SR Ca2+-ATP酶蛋白和兰尼碱受体2（RyR2）的表达，但降低了磷酸化-RyR2、Ca2+/钙调蛋白依赖性蛋白激酶II（CaMKII）和磷酸化-CaMKII的表达。结论：DAPA 通过恢复钙处理和抑制 ER 应激相关的 CM 凋亡，预防 β-AR 过度激活大鼠的心肌重塑和心功能障碍。