Direct Cardiac Actions of Sodium Glucose Cotransporter 2 Inhibitors Target Pathogenic Mechanisms Underlying Heart Failure in Diabetic Patients

作者：Laween Uthman, Antonius Baartscheer, Cees A. Schumacher, Jan W.T. Fiolet, Marius C. Kuschma, Markus W. Hollmann, Ruben Coronel, Nina C. Weber, Coert J. Zuurbier · 发表于：Frontiers in Physiology · 年份：2018 · DOI：10.3389/fphys.2018.01575 · 被引用次数：190 · 研究领域：Diabetes Treatment and Management、Pancreatic function and diabetes、Metabolism, Diabetes, and Cancer

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-re...