Dapagliflozin Ameliorates STZ-Induced Cardiac Hypertrophy in Type 2 Diabetic Rats by Inhibiting the Calpain-1 Expression and Nuclear Transfer of NF-κB.

Lei Liu,Jielong Tang,Yunyi Liang,Yi Shu,Haizhao Luo,Osamah Ibrahim Khalaf

doi:10.1155/2022/3293054

Abstract

Objective To investigate the effect of dapagliflozin (DAPA) on cardiac hypertrophy induced by type 2 diabetes mellitus (T2DM) and its mechanism. Methods SD rats with T2DM were divided into a T2DM group (n = 6) and DAPA group (n = 6). They were, respectively, fed with the same amount of normal saline and 1 mg/kg DAPA. The control group (n = 6) was also fed with normal saline. The hearts were tested by the application of echocardiography and hemodynamics. Subsequently, fasting blood glucose (FBG), serum total cholesterol (TC), and triglyceride (TG) as well as interleukin- (IL-) 10, IL-6, and tumor necrosis factor (TNF)-α in serum were tested. H&E and Masson staining was performed to observe the degree of cardiac tissue lesions, and expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), calpain-1, p-IκBα, and p65 in myocardial tissue was tested by qRT-PCR and Western blot. Results Compared with the control group, rats in the T2DM group exhibited significant diabetic symptoms: FBG was significantly elevated, and the levels of TC, TG, IL-6, and TNF-α were significantly increased, while the levels of IL-10 and the calpain activity were evidently decreased. However, DAPA treatment could improve the above changes. At the same time, the damage and fibrosis of the heart tissue in the DAPA group were markedly improved. Additionally, the mRNA expression of ANP and BNP in myocardial tissue of the DAPA group was markedly increased. And DAPA could inhibit the expression of p-IκBα/IκBα in the cytoplasm and p65 in the nucleus as well as the expression of calpain-1 in myocardial tissue. Conclusion DAPA treatment ameliorates the cardiac hypertrophy caused by T2DM by decreasing body blood glucose, while reducing the expression of calpain-1 in cardiomyocytes and inhibiting the nuclear translocation of NF-κB.

Highlights

Diabetes mellitus (DM) has become the most widespread disease in the 21st century [1]
Eighteen standard deviation (SD) rats (SPF grade) at 8 weeks of age, weighing 180~220 g, were selected. They were randomly divided into 3 groups, 6 rats in each group, which were the control group, type 2 diabetes mellitus (T2DM) group, and DAPA group. After the rats both in the T2DM group and DAPA group were fed high-fat and high-carbohydrate diet for 4 weeks, they were intraperitoneally injected with streptozotocin (STZ) 50 mg/kg. 72 h later, the fasting blood glucose (FBG) of rats was higher than 13.9 mmol/L while the random blood glucose was higher than 16.7 mmol/L which suggested that a rat model with T2DM was successfully conducted
The FBG level of rats in the T2DM group remained in the high glucose range, higher than 16.7 mmol/L even reaching at about 24 mmol/L

Summary

Introduction

Diabetes mellitus (DM) has become the most widespread disease in the 21st century [1]. Among numerous patients with DM, those with type 2 diabetes mellitus (T2DM) account for the majority, roughly reaching at 90% to 95% [3]. The main cause of death is heart disease induced by T2DM, known as diabetic cardiomyopathy (DCM) whose main manifestations are cardiac hypertrophy as well as myocardial interstitial remodeling and fibrosis [5]. Studies have reported that the core cause of heart failure in patients are cardiac dysfunctions due to left cardiac hypertrophy, for example, left ventricular ejection fraction (LVEF) left and ventricular systolic pressure (LVSP) [6]. Prevention or treatment of left cardiac hypertrophy in clinical practice is an important measure to prevent DCM from developing into heart failure

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Results

Conclusion