Dapagliflozin Improves Cardiac Function, Remodeling, Myocardial Apoptosis, and Inflammatory Cytokines in Mice with Myocardial Infarction

Abstract

Dapagliflozin (DAPA) exerts cardioprotective effects in non-diabetic patients. Nonetheless, the protective mechanism remains unknown. This study aims to evaluate the performance of DAPA on cardiac function and remodeling as well as its potential mechanism in mice with myocardial infarction (MI). Here, a MI mice model was established. One week after MI, mice were treated with saline or DAPA (1.5 mg/kg/day) for 4 weeks. At the end of this study, echocardiography was performed to assess cardiac structure and function. Myocardial apoptosis was analyzed by Western blot and immunofluorescence. Inflammatory cytokines and cardiac fibrosis were analyzed by real-time PCR and Masson's trichrome stain, respectively. Results showed that DAPA improved cardiac structure and function, attenuated cardiac fibrosis, and inhibited inflammatory cytokines and myocardial apoptosis. Moreover, the inhibition of PI3K/AKT/mTOR pathway might be related to the cardioprotective role of DAPA. These findings reveal that dapagliflozin is a potential therapeutic agent for MI patients without diabetes.

Appropriate Dose of Dapagliflozin Improves Cardiac Outcomes by Normalizing Mitochondrial Fission and Reducing Cardiomyocyte Apoptosis After Acute Myocardial Infarction

“… 34 Nonetheless, the dose and time for administering SGLT2i were still confused in clinical practice. A recent study published by Wang et al 21 revealed that DAPA could improve the cardiac function after MI via inhibiting the PI3K/AKT/mTOR pathway. However, the dose of DAPA they used was not intended for clinical practice in the real world.…”

“… 18 , 19 On the other hand, SGLT2i also exhibited markable anti-inflammatory effects by regulating the macrophage polarization via STAT3 signaling or inhibiting the PI3K/AKT/mTOR pathway in infarcted hearts without diabetes. 20 , 21 However, either DAPA or empagliflozin administered in the aforementioned studies were not quite suitable for clinical practice in dose and time, which may limit expanding its cardioprotective effects or finding the potential side effects. Recently, Liu et al 22 conducted an experiment with the purpose of exploring for a suitable dose of empagliflozin for MI without diabetes and found that 10 mg/kg per day of empagliflozin could also act as a cardioprotective role by inhibiting cardiomyocyte apoptosis and improving cardiac remodeling via activating AMPKα signaling pathway in the early phase of MI.…”

Suppression of Cardiogenic Edema with Sodium–Glucose Cotransporter-2 Inhibitors in Heart Failure with Reduced Ejection Fraction: Mechanisms and Insights from Pre-Clinical Studies

“…In an ischemic reperfusion (IR) model of pre-diabetic obese insulin-resistant Wistar rats on a high-fat diet, dapagliflozin improved LVEF [ 74 ]. In a post-MI HFrEF model: (1) empagliflozin treatment increased LVEF [ 72 ], improved contractility, stroke volume, and end-systolic blood pressure despite diuresis, and improved diastolic function (reduction in LV end-diastolic pressure) [ 75 ]; canagliflozin IR model treatment alleviated left ventricular (LV) systolic and diastolic dysfunction, which may be explained by the increased phosphorylation of adenosine monophosphate-activated protein kinase, eNOS, and subsequent vasodilation [ 76 ]; (2) in non-diabetic mice, dapagliflozin treatment improved LV systolic function and LV mass [ 77 ]. In an MI porcine model, empagliflozin treatment improved LV systolic function [ 61 ] and ameliorated diastolic dysfunction [ 78 ].…”

“…In a rat post-MI model of HFrEF, empagliflozin treatment attenuated cardiomyocyte hypertrophy and fibrosis [ 72 ], but did not show any improvement in interstitial fibrosis or cardiomyocyte hypertrophy in another study [ 75 ]. In a mouse post-MI HFrEF model: empagliflozin treatment improved cardiac remodeling by the inhibition of apoptosis, alleviated oxidative stress, restored mitochondrial membrane potential, and activated AMPK signaling [ 83 ]; dapagliflozin treatment inhibited cardiac apoptosis and reduced LV mass, the expression of cardiac collagen 1/3, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and transforming growth factor-β1 (TGF-β1) transcripts of cardiac fibrosis histological staining [ 77 ]. Treatment with empagliflozin (10 mg/kg/day) administered 3 weeks before MI improved cardiac remodeling and ameliorated fibrosis and hypertrophy post-MI in both diabetic and non-diabetic rats.…”

Anti-Arrhythmic Effects of Sodium-Glucose Co-Transporter 2 Inhibitors

“…SGLT2i have been reported to ameliorate inflammation (Lee et al, 2021;Wang et al, 2021). EMPA is shown to inhibit the increase of TNF-α and IL-6 levels in the cardiac tissue of Zucker diabetic fatty rats and patients with heart failure with preserved ejection fraction (HFpEF), and ameliorate microvascular inflammation (Kolijn et al, 2021).…”