Major clinical trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) exhibit protective effects against heart failure events, whereas inconsistencies regarding the cardiovascular death outcomes are observed. Therefore, we aimed to compare the selective SGLT-2i empagliflozin (EMPA), dapagliflozin (DAPA) and ertugliflozin (ERTU) in terms of infarct size (IS) reduction and to reveal the cardioprotective mechanism in healthy non-diabetic mice. C57BL/6 mice randomly received vehicle, EMPA (10 mg/kg/day) and DAPA or ERTU orally at the stoichiometrically equivalent dose (SED) for 7 days. 24 h-glucose urinary excretion was determined to verify SGLT-2 inhibition. IS of the region at risk was measured after 30 min ischemia (I), and 120 min reperfusion (R). In a second series, the ischemic myocardium was collected (10th min of R) for shotgun proteomics and evaluation of the cardioprotective signaling. In a third series, we evaluated the oxidative phosphorylation capacity (OXPHOS) and the mitochondrial fatty acid oxidation capacity by measuring the respiratory rates. Finally, Stattic, the STAT-3 inhibitor and wortmannin were administered in both EMPA and DAPA groups to establish causal relationships in the mechanism of protection. EMPA, DAPA and ERTU at the SED led to similar SGLT-2 inhibition as inferred by the significant increase in glucose excretion. EMPA and DAPA but not ERTU reduced IS. EMPA preserved mitochondrial functionality in complex I&II linked oxidative phosphorylation. EMPA and DAPA treatment led to NF-kB, RISK, STAT-3 activation and the downstream apoptosis reduction coinciding with IS reduction. Stattic and wortmannin attenuated the cardioprotection afforded by EMPA and DAPA. Among several upstream mediators, fibroblast growth factor-2 (FGF-2) and caveolin-3 were increased by EMPA and DAPA treatment. ERTU reduced IS only when given at the double dose of the SED (20 mg/kg/day). Short-term EMPA and DAPA, but not ERTU administration at the SED reduce IS in healthy non-diabetic mice. Cardioprotection is not correlated to SGLT-2 inhibition, is STAT-3 and PI3K dependent and associated with increased FGF-2 and Cav-3 expression.

钠葡萄糖共转运蛋白 2 抑制剂 (SGLT-2i) 的主要临床试验显示出对心力衰竭事件的保护作用，而观察到心血管死亡结果的不一致性。因此，我们旨在比较选择性 SGLT-2i 恩格列净 (EMPA)、达格列净 (DAPA) 和 ertugliflozin (ERTU) 在减少梗塞面积 (IS) 方面的作用，并揭示健康非糖尿病小鼠的心脏保护机制。C57BL/6 小鼠随机接受载体、EMPA（10 mg/kg/天）和 DAPA 或 ERTU，口服化学计量等效剂量 (SED)，持续 7 天。确定 24 小时葡萄糖尿排泄以验证 SGLT-2 抑制。在 30 分钟缺血 (I) 和 120 分钟再灌注 (R) 后测量风险区域的 IS。在第二个系列中，收集缺血心肌（R 的第 10 分钟）用于鸟枪法蛋白质组学和心脏保护信号传导的评估。在第三个系列中，我们通过测量呼吸频率来评估氧化磷酸化能力 (OXPHOS) 和线粒体脂肪酸氧化能力。最后，在 EMPA 和 DAPA 组中都施用 Stattic、STAT-3 抑制剂和渥曼青霉素，以建立保护机制中的因果关系。SED 的 EMPA、DAPA 和 ERTU 导致类似的 SGLT-2 抑制，正如葡萄糖排泄的显着增加所推断的那样。EMPA 和 DAPA 但不是 ERTU 降低了 IS。EMPA 在复杂的 I 和 II 连接的氧化磷酸化中保留了线粒体功能。EMPA 和 DAPA 处理导致 NF-kB、RISK、STAT-3 激活和下游细胞凋亡减少，同时 IS 减少。Stattic 和渥曼青霉素减弱了 EMPA 和 DAPA 提供的心脏保护作用。在几种上游介质中，EMPA 和 DAPA 处理增加了成纤维细胞生长因子 2 (FGF-2) 和小窝蛋白 3。ERTU 仅在以 SED 的双倍剂量（20 mg/kg/天）给药时才降低 IS。短期 EMPA 和 DAPA，而不是 ERTU 在 SED 管理减少健康非糖尿病小鼠的 IS。心脏保护作用与 SGLT-2 抑制无关，依赖于 STAT-3 和 PI3K，并与 FGF-2 和 Cav-3 表达增加有关。但在 SED 中使用 ERTU 不会降低健康非糖尿病小鼠的 IS。心脏保护作用与 SGLT-2 抑制无关，依赖于 STAT-3 和 PI3K，并与 FGF-2 和 Cav-3 表达增加有关。但在 SED 中使用 ERTU 不会降低健康非糖尿病小鼠的 IS。心脏保护作用与 SGLT-2 抑制无关，依赖于 STAT-3 和 PI3K，并与 FGF-2 和 Cav-3 表达增加有关。