Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a.

Jana Goerg,Elena Kaschina,Alexander Kulikov,Ulrich Kintscher,Manuela Sommerfeld,Yasemin Seckin,Bettina Greiner,Dilyara Lauer,Dmitry Ivkin,Sergey Okovityi

doi:10.3390/ijms22115437

Abstract

The effects of the selective sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in low dose on cardiac function were investigated in normoglycemic rats. Cardiac parameters were measured by intracardiac catheterization 30 min after intravenous application of empagliflozin to healthy animals. Empagliflozin increased the ventricular systolic pressure, mean pressure, and the max dP/dt (p < 0.05). Similarly, treatment with empagliflozin (1 mg/kg, p.o.) for one week increased the cardiac output, stroke volume, and fractional shortening (p < 0.05). Myocardial infarction (MI) was induced by ligation of the left coronary artery. On day 7 post MI, empagliflozin (1 mg/kg, p.o.) improved the systolic heart function as shown by the global longitudinal strain (−21.0 ± 1.1% vs. −16.6 ± 0.7% in vehicle; p < 0.05). In peri-infarct tissues, empagliflozin decreased the protein expression of matrix metalloproteinase 9 (MMP9) and favorably regulated the cardiac transporters sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and sodium hydrogen exchanger 1 (NHE1). In H9c2 cardiac cells, empagliflozin decreased the MMP2,9 activity and prevented apoptosis. Empagliflozin did not alter the arterial stiffness, blood pressure, markers of fibrosis, and necroptosis. Altogether, short-term treatment with low-dose empagliflozin increased the cardiac contractility in normoglycemic rats and improved the systolic heart function in the early phase after MI. These effects are attributed to a down-regulation of MMP9 and NHE1, and an up-regulation of SERCA2a. This study is of clinical importance because it suggests that a low-dose treatment option with empagliflozin may improve cardiovascular outcomes post-MI. Down-regulation of MMPs could be relevant to many remodeling processes including cancer disease.

Highlights

IntroductionRecent clinical studies demonstrated favorable cardiovascular effects of the antidiabetic drugs from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, including a reduction of cardiovascular death, non-fatal myocardial infarction (MI), heart failure, and non-fatal stroke, as well as all-cause mortality [1,2,3,4,5,6]
Cardiac contractility was improved in heart failure with preserved and reduced ejection fractions [7,8,9,10,11], in ischemia/reperfusion [12], myocardial infarction (MI) models [13,14,15,16,17], and diabetic cardiomyopathy [18]
The application of Empa in a low dose in the sham group showed an increase in cardiac output, stroke volume, and fractional shortening

Summary

Introduction

Recent clinical studies demonstrated favorable cardiovascular effects of the antidiabetic drugs from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, including a reduction of cardiovascular death, non-fatal myocardial infarction (MI), heart failure, and non-fatal stroke, as well as all-cause mortality [1,2,3,4,5,6]. Cardiac contractility was improved in heart failure with preserved and reduced ejection fractions [7,8,9,10,11], in ischemia/reperfusion [12], MI models [13,14,15,16,17], and diabetic cardiomyopathy [18]. The antiarrhythmic properties of SGLT2 inhibitors were shown in the ischemia-reperfusion model [19] and atrial fibrillation [20]. The exact cardio-protective mechanism of action is still unclear—especially since SGLT2 receptors are not expressed in the heart [22,23]

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Discussion

Conclusion