Comparative efficacy of empagliflozin and drugs of baseline therapy in post-infarct heart failure in normoglycemic rats

Краснова, М. В.; Kulikov, A. N.; Оковитый, С. В.; Ивкин, Д. Ю.; Карпов, А. А.; Kaschina, Elena; Смирнов, А. В.

doi:10.1007/s00210-020-01873-7

Cited by 12 publications

(10 citation statements)

References 32 publications

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“…But, the exercise tolerance was observably decreased. Therefore, it was concluded that compared with fosinopril, empagliflozin reduced the progression of left ventricular dysfunction and improved tolerance to physical exercise in rats with HF (Krasnova et al 2020 ). Thus, for normoglycemic and non-hypertensive rats, empagliflozin could get more cardiac benefits than antihypertensive when it did not need blood pressure therapy or hypoglycemic agent.…”

Section: Discussionmentioning

confidence: 99%

Canagliflozin mitigates ferroptosis and ameliorates heart failure in rats with preserved ejection fraction

Zhang

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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Recently, hypoglycemic drugs belonging to sodium-glucose cotransporter 2 inhibitors (SGLT2i) have generated significant interest due to their clear cardiovascular benefits for heart failure with preserved ejection fraction (HFpEF) since there are no effective drugs that may improve clinical outcomes for these patients over a prolonged period. But, the underlying mechanisms remain unclear, particularly its effects on ferroptosis, a newly defined mechanism of iron-dependent non-apoptotic cell death during heart failure (HF). Here, with proteomics, we demonstrated that ferroptosis might be a key mechanism in a rat model of high-salt diet-induced HFpEF, characterized by iron overloading and lipid peroxidation, which was blocked following treatment with canagliflozin. Data are available via ProteomeXchange with identifier PXD029031. The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4, glutathione peroxidase 4, ferritin heavy chain 1, transferrin receptor, Ferroportin 1, iron, glutathione, malondialdehyde, and 4-hydroxy-trans-2-nonenal. These findings highlight the fact that targeting ferroptosis may serve as a cardioprotective strategy for HFpEF prevention and suggest that canagliflozin may exert its cardiovascular benefits partly via its mitigation of ferroptosis.

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Section: Discussionmentioning

confidence: 99%

Canagliflozin mitigates ferroptosis and ameliorates heart failure in rats with preserved ejection fraction

Zhang

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Accumulating experimental evidence has confirmed the benefits of SGLT2 inhibitors in various animal models, showing their favorable role in reducing the development and progression of cardiovascular diseases. For example, the cardioprotective effects of empagliflozin were attributed to the alleviation of atrial remodeling in high-fat diet/streptozotocin-induced diabetic rats [ 8 ], improvement of myocardial energetics in non-diabetic heart failure pigs [ 28 ], prevention of cardiac remodeling, endothelial dysfunction and attenuation of cardiac fibrosis in the metabolic syndrome ZSF1 rat [ 5 ], non-diabetic post-infarct rats with either LV dysfunction [ 29 ] or heart failure [ 30 ], and also in hypertensive heart failure rats [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death

et al. 2021

Cardiovasc Diabetol

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Background Empagliflozin is a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor used to lower blood sugar in adults with type 2 diabetes. Empagliflozin also exerts cardioprotective effects independent from glucose control, but its benefits on arrhythmogenesis and sudden cardiac death are not known. The purpose of this study was to examine the effect of empagliflozin on myocardial ischemia/reperfusion-provoked cardiac arrhythmia and sudden cardiac death in vivo. Methods Male Sprague Dawley rats were randomly assigned to sham-operated, control or empagliflozin groups. All except for the sham-operated rats were subjected to 5-min left main coronary artery ligation followed by 20-min reperfusion. A standard limb lead II electrocardiogram was continuously measured throughout the experiment. Coronary artery reperfusion-induced ventricular arrhythmogenesis and empagliflozin therapy were evaluated. The hearts were used for protein phosphorylation analysis and immunohistological assessment. Results Empagliflozin did not alter baseline cardiac normal conduction activity. However, empagliflozin eliminated myocardial vulnerability to sudden cardiac death (from 69.2% mortality rate in the control group to 0% in the empagliflozin group) and reduced the susceptibility to reperfusion-induced arrhythmias post I/R injury. Empagliflozin increased phosphorylation of cardiac ERK1/2 after reperfusion injury. Furthermore, inhibition of ERK1/2 using U0126 abolished the anti-arrhythmic action of empagliflozin and ERK1/2 phosphorylation. Conclusions Pretreatment with empagliflozin protects the heart from subsequent severe lethal ventricular arrhythmia induced by myocardial ischemia and reperfusion injury. These protective benefits may occur as a consequence of activation of the ERK1/2-dependent cell-survival signaling pathway in a glucose-independent manner.

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“…SGLT2 inhibitors earned great attention from investigators due to the recently discovered pleiotropic cardioprotective effects. Besides favorable actions on the heart by treating diabetes [ 1 , 26 ], SGLT2 inhibitors also protected normoglycemic animals in heart failure models [ 7 , 8 , 10 , 11 ], myocardial infarction [ 13 , 14 ], and occlusion/reperfusion models [ 12 ]. Nevertheless, in clinical [ 4 , 5 ] and experimental [ 7 , 8 , 14 ] studies, there are controversial issues regarding systolic and diastolic heart function improvement.…”

Section: Discussionmentioning

confidence: 99%

“…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 ]. In experimental models, 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 ]. Recently, the antiarrhythmic properties of SGLT2 inhibitors were shown in the ischemia-reperfusion model [ 19 ] and atrial fibrillation [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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

Goerg

Sommerfeld

Greiner

et al. 2021

IJMS

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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.

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Comparative efficacy of empagliflozin and drugs of baseline therapy in post-infarct heart failure in normoglycemic rats

Cited by 12 publications

References 32 publications

Canagliflozin mitigates ferroptosis and ameliorates heart failure in rats with preserved ejection fraction

Canagliflozin mitigates ferroptosis and ameliorates heart failure in rats with preserved ejection fraction

Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death

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

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