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

• Published in: International journal of molecular sciences 2019-04, Vol.20 (7), p.1680
• Main Authors: Lee, Ting-I, Chen, Yao-Chang, Lin, Yung-Kuo, Chung, Cheng-Chih, Lu, Yen-Yu, Kao, Yu-Hsun, Chen, Yi-Jen
• Format: Article
• Language: English
• Subjects: Animals; Benzhydryl Compounds - therapeutic use; Blood; Body size; Body weight; Calcium - metabolism; calcium handling; Calcium homeostasis; Calcium ions; Cardiac muscle; cardiomyocytes; Cardiomyopathy; Cell size; Diabetes mellitus; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; EKG; Electrocardiography; Electrophysiology; Glucosides - therapeutic use; Heart; Homeostasis; Hypertension; Myocardium - metabolism; Myocytes; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Oxidative stress; Potassium; Rats; Rodents; Ryanodine Receptor Calcium Release Channel - metabolism; Signal transduction; Sodium; Sodium - metabolism; Sodium glucose co-transporter 2 inhibitor; sodium regulation; Sodium-Calcium Exchanger - metabolism; Streptozocin; Ventricle
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20071680

Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca ) 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 Ca /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 Ca contents, intracellular Ca transients, L-type Ca , reverse mode Na⁺-Ca 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 Ca 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 Ca regulation, late Na⁺ and Na⁺/hydrogen-exchanger currents and electrophysiological characteristics in DM cardiomyopathy, which may contribute to its cardioprotective benefits in DM patients.