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Front. Physiol. | doi: 10.3389/fphys.2018.01575

Direct cardiac actions of sodium glucose cotransporter 2 inhibitors target pathogenic mechanisms underlying heart failure in diabetic patients

 Laween Uthman1, 2, 3, 4, 5,  Antonius Baartscheer1, 2, 3, 4, Cees A. Schumacher1, 2, 3, 4, Jan W. Fiolet2,  Marius C. Kuschma1, 2, 3, 4, 5, Markus W. Hollmann1, 2, 3, 4, 5, Ruben Coronel1, 2, 3, 4, 6,  Nina C. Hauck-Weber1, 2, 3, 4, 5 and  Coert J. Zuurbier1, 2, 3, 4, 5*
  • 1Laboratory of Experimental Intensive Care and Anesthesiology, Anesthesiology, Academic Medical Center (AMC), Netherlands
  • 2Clinical and Experimental Cardiology; Amsterdam Cardiovascular Sciences, Academic Medical Center (AMC), Netherlands
  • 3University of Amsterdam, Netherlands
  • 4Amsterdam Cardiovascular Sciences, Netherlands
  • 5Amsterdam Infection & Immunity Institute, Netherlands
  • 6IHU Lyric - L'Institut de rythmologie et modélisation cardiaque, France

Sodium glucose cotransporter 2 inhibitors (SGLT2i) are the first antidiabetic compounds that effectively reduce heart failure hospitalization and cardiovascular death in type 2 diabetics. SGLT2i were designed to decrease serum glucose levels by inhibiting SGLT2 in the kidney and to induce glycosuria. Direct off-target cardiac actions of SGLT2i have recently been documented. Here, we review the effects of SGLT2i on the various cardiac cell types and on cardiac function, and discuss how these may contribute to the cardiovascular benefits observed in large clinical trials.
SGLT2i impaired the Na+/H+ exchanger (NHE-1) and reduced cytosolic [Ca2+] and [Na+] in cardiomyocytes. In addition, Empagliflozin (Empa), one of the best studied SGLT2i, increased myocardial mitochondrial calcium. Empa also maintained cell viability and ATP content following hypoxia/reoxygenation in cardiomyocytes and endothelial cells. Hyperglycemia-induced eNOS reduction was alleviated by Empa in human umbilical vein endothelial cells (HUVEC), and a different SGLT2i Dapagliflozin (Dapa) improved vasorelaxation in hyperglycemic and TNF-α stimulated aortic rings. Attenuation of vascular dysfunction by Empa, Dapa and Canagliflozin (Cana) in hyperglycemic aortic rings was observed. Anti-inflammatory actions of Cana in IL-1ß-treated HUVEC and of Dapa in LPS-treated cardiofibroblast were mediated, at least partly, by AMPK activation.
In isolated mouse hearts, both Empa and Cana induced vasodilation. In ischemia-reperfusion studies of the isolated heart, Empa delayed contracture development during ischemia and increased mitochondrial respiration post-ischemia.
Because increased cardiac cytosolic [Ca2+] and [Na+], NHE-1 activation, elevated inflammation, impaired vasorelaxation and reduced AMPK activity are common in diabetic and failing hearts and because antagonizing these changes has been associated with improved cardiac function, the direct cardiovascular effects of SGLT2i may have large clinical impact.

Keywords: SGLT2 inhibitors (SGLT2-i), cardiomyocyte, Endothelial cell (EC), smooth musce cell, cardiac fibroblast, Isolated heart, Type 2 Ddiabetes mellitus, Heart failiure

Received: 31 Jul 2018; Accepted: 22 Oct 2018.

Edited by:

Gaetano Santulli, Columbia University, United States

Reviewed by:

Wayne R. Giles, University of Calgary, Canada
Xiaoqiang Tang, Sichuan University, China  

Copyright: © 2018 Uthman, Baartscheer, Schumacher, Fiolet, Kuschma, Hollmann, Coronel, Hauck-Weber and Zuurbier. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Coert J. Zuurbier, Academic Medical Center (AMC), Laboratory of Experimental Intensive Care and Anesthesiology, Anesthesiology, Amsterdam, Netherlands,