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Open AccessArticle

Empagliflozin Attenuates Myocardial Sodium and Calcium Dysregulation and Reverses Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats

1
Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
2
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
4
Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan
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Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
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Division of Cardiology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei City 22174, Taiwan
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School of Medicine, Fu-Jen Catholic University, New Taipei City 22174, Taiwan
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Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
9
Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(7), 1680; https://doi.org/10.3390/ijms20071680
Received: 18 February 2019 / Revised: 30 March 2019 / Accepted: 2 April 2019 / Published: 4 April 2019
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca2+) and sodium (Na+) regulation. Clinical studies have shown that empagliflozin (Jardiance™) has cardiovascular benefits, however the mechanisms have not been fully elucidated. This study aimed to investigate whether empagliflozin modulates cardiac electrical activity as well as Ca2+/Na+ homeostasis in DM cardiomyopathy. Electrocardiography, echocardiography, whole-cell patch-clamp, confocal microscopic examinations, and Western blot, were performed in the ventricular myocytes of control and streptozotocin-induced DM rats, with or without empagliflozin (10 mg/kg for 4 weeks). The results showed that the control and empagliflozin-treated DM rats had smaller left ventricular end-diastolic diameters and shorter QT intervals than the DM rats. In addition, the prolonged action potential duration in the DM rats was attenuated in the empagliflozin-treated DM rats. Moreover, the DM rats had smaller sarcoplasmic reticular Ca2+ contents, intracellular Ca2+ transients, L-type Ca2+, reverse mode Na+-Ca2+exchanger currents, lower protein expressions of sarcoplasmic reticulum ATPase, ryanodine receptor 2 (RyR2), but higher protein expressions of phosphorylated RyR2 at serine 2808 than the control and empagliflozin-treated DM rats. The incidence and frequency of Ca2+ sparks, cytosolic and mitochondrial reactive oxygen species, and late Na+ current and Na+/hydrogen-exchanger currents were greater in the DM rats than in the control and empagliflozin-treated DM rats. Empagliflozin significantly changed Ca2+ regulation, late Na+ and Na+/hydrogen-exchanger currents and electrophysiological characteristics in DM cardiomyopathy, which may contribute to its cardioprotective benefits in DM patients. View Full-Text
Keywords: Sodium glucose co-transporter 2 inhibitor; diabetes mellitus; calcium handling; sodium regulation; cardiomyocytes Sodium glucose co-transporter 2 inhibitor; diabetes mellitus; calcium handling; sodium regulation; cardiomyocytes
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MDPI and ACS Style

Lee, T.-I.; Chen, Y.-C.; Lin, Y.-K.; Chung, C.-C.; Lu, Y.-Y.; Kao, Y.-H.; Chen, Y.-J. Empagliflozin Attenuates Myocardial Sodium and Calcium Dysregulation and Reverses Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats. Int. J. Mol. Sci. 2019, 20, 1680.

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