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Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure

文献类型：期刊论文

作者Li, Xuan1; Lu, Qingguo1,2; Qiu, Yunguang3,4; do Carmo, Jussara M.1; Wang, Zhen1; da Silva, Alexandre A.1; Mouton, Alan1; Omoto, Ana C. M.1; Hall, Michael E.1; Li, Ji5
刊名JOURNAL OF THE AMERICAN HEART ASSOCIATION
出版日期2021-03-16
卷号10期号:6页码:33
ISSN号2047-9980
关键词cardiac hypertrophy cardiac metabolism cardiomyocytes sodium glucose cotransporter 2 transverse aortic constriction
DOI10.1161/JAHA.120.018298
通讯作者Li, Xuan(xli3@umc.edu)
英文摘要Background 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. Methods and Results 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. Conclusions 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.
资助项目National Heart, Lung, and Blood Institute of the National Institutes of Health[P01HL051971] ; National Institute of General Medical Sciences[P20GM104357] ; National Institute of General Medical Sciences[U54GM115428] ; National Institute of General Medical Sciences[R01GM124108] ; National Institute of Diabetes and Digestive and Kidney Diseases[R01 DK121411] ; National Institute of Diabetes and Digestive and Kidney Diseases[R00 DK113280] ; National Institute on Aging[R01AG049835]
WOS研究方向Cardiovascular System & Cardiology
语种英语
出版者WILEY
WOS记录号WOS:000630047500044
源URL[http://119.78.100.183/handle/2S10ELR8/295354]  
专题新药研究国家重点实验室
通讯作者Li, Xuan
作者单位1.Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Mississippi Ctr Obes Res,Mississippi Ctr Heart Re, Jackson, MS 39216 USA
2.Sichuan Univ, Dept Endocrinol & Metab, West China Hosp, Chengdu, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
5.Univ S Florida, Dept Surg, Tampa, FL 33620 USA
推荐引用方式
GB/T 7714		 Li, Xuan,Lu, Qingguo,Qiu, Yunguang,et al. Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure[J]. JOURNAL OF THE AMERICAN HEART ASSOCIATION,2021,10(6):33.
APA Li, Xuan.,Lu, Qingguo.,Qiu, Yunguang.,do Carmo, Jussara M..,Wang, Zhen.,...&Hall, John E..(2021).Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure.JOURNAL OF THE AMERICAN HEART ASSOCIATION,10(6),33.
MLA Li, Xuan,et al."Direct Cardiac Actions of the Sodium Glucose Co-Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure-Overload Heart Failure".JOURNAL OF THE AMERICAN HEART ASSOCIATION 10.6(2021):33.

入库方式： OAI收割

来源：上海药物研究所

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