Cardioprotective effects of empagliflozin after ischemia and reperfusion in rats

被引:28
作者
Seefeldt, Jacob Marthinsen [1 ,2 ,4 ]
Lassen, Thomas Ravn [1 ]
Hjortbak, Marie Vognstoft [1 ,2 ]
Jespersen, Nichlas Riise [1 ]
Kvist, Frederikke [1 ,2 ]
Hansen, Jakob [2 ,3 ]
Botker, Hans Erik [1 ,2 ]
机构
[1] Aarhus Univ Hosp, Dept Cardiol, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark
[2] Aarhus Univ, Dept Clin Med, Palle Juul Jensens Blvd 82, DK-8200 Aarhus N, Denmark
[3] Aarhus Univ Hosp, Dept Forens Med, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark
[4] Thunogade 30,St Tv, DK-8000 Aarhus C, Denmark
关键词
IN-VIVO; MYOCARDIAL-INFARCTION; OXIDATIVE-PHOSPHORYLATION; OUTCOMES; CANAGLIFLOZIN; INHIBITOR; SIZE;
D O I
10.1038/s41598-021-89149-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The Sodium Glucose Co-Transporter-2 inhibitor, empagliflozin (EMPA), reduces mortality and hospitalisation for heart failure following myocardial infarction irrespective of diabetes status. While the findings suggest an inherent cardioprotective capacity, the mechanism remains unknown. We studied infarct size (IS) ex-vivo in isolated hearts exposed to global IR injury and in-vivo in rats subjected to regional myocardial ischemia reperfusion (IR) injury, in whom we followed left ventricular dysfunction for 28 days. We compared rats that were given EMPA orally for 7 days before, EMPA 1.5 h before IR injury and at onset of reperfusion and continued orally during the follow-up period. We used echocardiography, high resolution respirometry, microdialysis and plasma levels of beta-hydroxybutyrate to assess myocardial performance, mitochondrial respiration and intermediary metabolism, respectively. Pretreatment with EMPA for 7 days reduced IS in-vivo (65 +/- 7% vs. 46 +/- 8%, p < 0.0001 while administration 1.5 h before IR, at onset of reperfusion or ex-vivo did not. EMPA alleviated LV dysfunction irrespective of the reduction in IS. EMPA improved mitochondrial respiration and modulated myocardial interstitial metabolism while the concentration of beta-hydroxybutyric acid was only transiently increased without any association with IS reduction. EMPA reduces infarct size and yields cardioprotection in non-diabetic rats with ischemic LV dysfunction by an indirect, delayed intrinsic mechanism that also improves systolic function beyond infarct size reduction. The mechanism involves enhanced mitochondrial respiratory capacity and modulated myocardial metabolism but not hyperketonemia.
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页数:13
相关论文
共 37 条
[1]   Empagliflozin Limits Myocardial Infarction in Vivo and Cell Death in Vitro: Role of STAT3, Mitochondria, and Redox Aspects [J].
Andreadou, Ioanna ;
Efentakis, Panagiotis ;
Balafas, Evangelos ;
Togliatto, Gabriele ;
Davos, Constantinos H. ;
Varela, Aimilia ;
Dimitriou, Constantinos A. ;
Nikolaou, Panagiota-Efstathia ;
Maratou, Eirini ;
Lambadiari, Vaia ;
Ikonomidis, Ignatios ;
Kostomitsopoulos, Nikolaos ;
Brizzi, Maria F. ;
Dimitriadis, George ;
Iliodromitis, Efstathios K. .
FRONTIERS IN PHYSIOLOGY, 2017, 8
[2]   Inhibition of sodium-glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization [J].
Baker, Hana E. ;
Kiel, Alexander M. ;
Luebbe, Samuel T. ;
Simon, Blake R. ;
Earl, Conner C. ;
Regmi, Ajit ;
Roell, William C. ;
Mather, Kieren J. ;
Tune, Johnathan D. ;
Goodwill, Adam G. .
BASIC RESEARCH IN CARDIOLOGY, 2019, 114 (03)
[3]   A UPLC-MS/MS application for profiling of intermediary energy metabolites in microdialysis samples-A method for high-throughput [J].
Birkler, Rune Isak Dupont ;
Stottrup, Nicolaj Brejnholt ;
Hermannson, Sigurd ;
Nielsen, Torsten Toftegaard ;
Gregersen, Niels ;
Botker, Hans Erik ;
Andreasen, Mette Findal ;
Johannsen, Mogens .
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 2010, 53 (04) :983-990
[4]   Nonclinical Safety of the Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin [J].
Bogdanffy, Matthew S. ;
Stachlewitz, Robert F. ;
van Tongeren, Susan ;
Knight, Brian ;
Sharp, Dale E. ;
Ku, Warren ;
Hart, Susan Emeigh ;
Blanchard, Kerry .
INTERNATIONAL JOURNAL OF TOXICOLOGY, 2014, 33 (06) :436-449
[5]   Anesthetic-induced preconditioning - Previous administration of isoflurane decreases myocardial infarct size in rabbits [J].
Cason, BA ;
Gamperl, AK ;
Slocum, RE ;
Hickey, RF .
ANESTHESIOLOGY, 1997, 87 (05) :1182-1190
[6]   National Trends in Heart Failure Hospitalization After Acute Myocardial Infarction for Medicare Beneficiaries 1998-2010 [J].
Chen, Jersey ;
Hsieh, Angela Fu-Chi ;
Dharmarajan, Kumar ;
Masoudi, Frederick A. ;
Krumholz, Harlan M. .
CIRCULATION, 2013, 128 (24) :2577-2584
[7]  
(CHMP) CfMPfHU, 2014, ASS REP EB
[8]   Impaired cardiac mitochondrial oxidative phosphorylation and enhanced mitochondrial oxidative stress in feline hypertrophic cardiomyopathy [J].
Christiansen, Liselotte B. ;
Dela, Flemming ;
Koch, Jorgen ;
Hansen, Christina N. ;
Leifsson, Pall S. ;
Yokota, Takashi .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2015, 308 (10) :H1237-H1247
[9]  
Council FMNR, 1996, GUIDE CARE USE LAB A, DOI [10.17226/5140, DOI 10.17226/5140]
[10]   CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis [J].
Ferrannini, Ele ;
Mark, Michael ;
Mayoux, Eric .
DIABETES CARE, 2016, 39 (07) :1108-1114