Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure.
Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure.
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DOI：
10.1161/jaha.120.018298
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发表时间：
2021-03-16
影响因子：
5.4
通讯作者：
Hall JE
中科院分区：
文献类型：
--
作者：
Li X;Lu Q;Qiu Y;do Carmo JM;Wang Z;da Silva AA;Mouton A;Omoto ACM;Hall ME;Li J;Hall JE
我们确定了葡萄糖协同转运蛋白2的钠离子转运体2抑制剂依帕格列酮是否通过直接心脏效应减轻非糖尿病小鼠压力超负荷所致的心力衰竭，并探讨了相关机制。雄性C57BL/6J小鼠(4~6个月龄)采用假手术或横断胸主动脉缩窄的方法造成心脏压力超负荷。腹主动脉缩窄后2周，每日给予依帕格列酮(10 mg/kg/d)或赋形剂，连续4周。依帕格列酮可提高存活率，显著减轻横断性主动脉缩窄后不良的左心室重构和心肌纤维化。根据超声心动图的评估，依帕格列酮还可以减轻心脏收缩和舒张期功能障碍，并使横状主动脉缩窄所致心力衰竭小鼠的运动耐力提高36%。依帕格列酮显著增加衰竭心脏的葡萄糖和脂肪酸氧化，同时减少糖酵解。在空腹血糖、体重或每日尿量没有显著变化的情况下，依帕格列酮对心脏的这些有益作用仍会发生。体外分离的心肌细胞实验表明，依帕格列酮具有直接改善心肌细胞收缩和钙瞬变的作用。重要的是，分子对接分析和离体灌流心脏实验表明，依帕格列酮可以结合心肌葡萄糖转运体，减少糖酵解，恢复一磷酸腺苷激活的蛋白激酶的激活，并抑制雷帕霉素复合体1通路的哺乳动物靶点的激活。我们的研究表明，埃帕利福秦可能直接结合葡萄糖转运蛋白来减少糖酵解，重新平衡糖酵解和氧化磷酸化之间的偶联，并调节雷帕霉素复合体1通路的哺乳动物靶标一磷酸腺苷激活的蛋白激酶，以减轻非糖尿病小鼠压力超负荷导致的不利心脏重构和心力衰竭的进展。
We determined if the sodium glucose co‐transporter 2 inhibitor empagliflozin attenuates pressure overload‐induced heart failure in non‐diabetic mellitus mice by direct cardiac effects and the mechanisms involved. Male C57BL/6J mice (4–6 months of age) were subjected to sham surgeries or transverse aortic constriction to produce cardiac pressure overload. Two weeks after transverse aortic constriction, empagliflozin (10 mg/kg per day) or vehicle was administered daily for 4 weeks. Empagliflozin increased survival rate and significantly attenuated adverse left ventricle remodeling and cardiac fibrosis after transverse aortic constriction. Empagliflozin also attenuated left ventricular systolic and diastolic dysfunction, evaluated by echocardiography, and increased exercise endurance by 36% in mice with transverse aortic constriction‐induced heart failure. Empagliflozin significantly increased glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. These beneficial cardiac effects of empagliflozin occurred despite no significant changes in fasting blood glucose, body weight, or daily urine volume. In vitro experiments in isolated cardiomyocytes indicated that empagliflozin had direct effects to improve cardiomyocyte contractility and calcium transients. Importantly, molecular docking analysis and isolated perfused heart experiments indicated that empagliflozin can bind cardiac glucose transporters to reduce glycolysis, restore activation of adenosine monophosphate‐activated protein kinase and inhibit activation of the mammalian target of rapamycin complex 1 pathway. Our study demonstrates that empagliflozin may directly bind glucose transporters to reduce glycolysis, rebalance coupling between glycolysis and oxidative phosphorylation, and regulate the adenosine monophosphate‐activated protein kinase mammalian target of rapamycin complex 1 pathway to attenuate adverse cardiac remodeling and progression of heart failure induced by pressure‐overload in non‐diabetic mellitus mice.