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

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.

Direct cardiac effects of SGLT2 inhibitors

“…In H9C2 cardiac cells, EMPA (1 μM) in the presence of albumin decreased the matrix metalloprotease (MMP)2 and MMP9 activity induced by IL-1 alpha and prevented apoptosis [ 35 ]. CANA (3 μM) in the presence of albumin was able to reduce ROS production in human right and left atrial tissue and cultured cells through inhibition of a SGLT1/AMPK/Rac1/NADPH oxidase pathway, whereas EMPA was without any effect [ 36 ].…”

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

“…MMP9, also known as gelatinase B, can degrade elastin and collagen and is involved in inflammatory responses, and is one of the most extensively studied MMPs in cardiovascular and renal research ( 81 , 82 ). Low-dose empagliflozin can improve systolic heart function after MI in rats by regulating MMP9 ( 83 ). Luseogliflozin regulates the expression of multiple mRNA, including MMP9, and inhibits the progression of atherosclerosis in diabetic APOE-deficient mice ( 84 ).…”

Identification of hub genes and their correlation with immune infiltration in coronary artery disease through bioinformatics and machine learning methods

“…MMP9 also plays an important role in disease processes, including in embryonic development, reproduction tissue remodeling, arthritis, and metastasis (33). Goerg et al (34) reported that downregulation of MMP9 protein expression in (35). PELI1 can facilitate the activity of ubiquitin protein ligase, and it participates in negative regulation of necroptotic procedure, protein polyubiquitination, and reaction to LPS (36).…”

“…MMP9 also plays an important role in disease processes, including in embryonic development, reproduction tissue remodeling, arthritis, and metastasis ( 33 ). Goerg et al ( 34 ) reported that downregulation of MMP9 protein expression in the heart by empagliflozin could improve systolic heart function after myocardial infarction (MI) in rats. A study by Mujumdar et al demonstrated that the activation of MMP9 decreased cardiac tensile strength ( 35 ).…”