Empagliflozin Ameliorates Diabetic Cardiomyopathy via Attenuating Oxidative Stress and Improving Mitochondrial Function

Abstract

Diabetic cardiomyopathy (DCM) is considered to be a critical contributor to the development of heart failure. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has been shown to prevent cardiovascular events and reduce the incidence of heart failure in randomized clinical trials. However, the mechanism of how EMPA prevents DCM is poorly understood. To study the potential mechanisms involved in the therapeutic effects of EMPA, we assessed the protective effects of EMPA on myocardial injury in type 2 diabetic db/db mice and H9C2 cardiomyocytes. 9–10-week-old male db/db mice were treated with EMPA (10 mg/kg) via oral gavage daily for 20 weeks. Afterward, cardiac function of treated mice was evaluated by echocardiography, and pathological changes in heart tissues were determined by histopathological examination and western blot assay. EMPA markedly reduced blood glucose levels, improved insulin tolerance, and enhanced insulin sensitivity of db/db mice. In addition, EMPA significantly prevented cardiac dysfunction, inhibited cardiac hypertrophy and fibrosis, and reduced glycogen deposition in heart tissues. Furthermore, EMPA improved diabetes-induced oxidative stress and mitochondrial dysfunction in both heart tissues of db/db mice and palmitate exposed H9C2 cells. EMPA significantly increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream genetic targets in cardiac tissue of type 2 diabetic db/db mice and H9C2 cells. EMPA also downregulated the expression of mitochondrial fission-related proteins and upregulated the expression of mitochondrial fusion-related proteins. Collectively, these findings indicate that EMPA may prevent DCM via attenuating oxidative stress and improving mitochondrial function in heart tissue.

The Importance of SGLT-2 Inhibitors as Both the Prevention and the Treatment of Diabetic Cardiomyopathy

“…Another antioxidative property presented by empagliflozin involves suppressing NOX4 and attenuating oxidation products. The study by Wang et al showed an intensified expression of Nrf2 and HO-1 protein, which was impaired in non-treated diabetic groups, and the promotion of Nrf2 nuclear translocation in the empagliflozin group [ 83 , 110 ]. Wang et al also described cardio-protective effects of empagliflozin treatment studied in both db/db mice and palmitate-exposed H9C2 cardiomyocytes, which include attenuating of cardiac remodelling, increasing sensitivity to insulin and supporting mitochondrial activity.…”

“…Wang et al also described cardio-protective effects of empagliflozin treatment studied in both db/db mice and palmitate-exposed H9C2 cardiomyocytes, which include attenuating of cardiac remodelling, increasing sensitivity to insulin and supporting mitochondrial activity. The ability to promote Nrf2 is one of the factors that determines antioxidative properties of empagliflozin and, overall, stands for a compound process of preventing diabetic cardiomyopathy [ 110 ].…”

Potential Mechanisms of Yiqi Jiedu Huayu Decoction in the Treatment of Diabetic Microvascular Complications Based on Network Analysis, Molecular Docking, and Experimental Validation

“…To further analyze the role of genes in pathways, Hub genes were mapped in the KEGG pathways. A total of 28 rats were randomly divided into three groups: normal control group (8), diabetic group (10), and YJHD group (10). To construct the diabetic rat models, streptozotocin dissolved in citric acid solution was injected into the peritoneal cavity of the rats in the diabetic and YJHD groups at a dose of 60 mg/kg [12].…”

“…Pathological changes in DCM include myocardial fbrosis, left ventricular hypertrophy, and impaired left ventricular systolic and diastolic function. Without effective treatment, these pathological changes will eventually lead to cardiac dysfunction, heart failure, and even death [8,9]. At least about 30% of diabetic patients sufer from DN [10].…”

The effect of EMPAgliflozin on markers of inflammation in patients with concomitant type 2 diabetes mellitus and Coronary ARtery Disease: the EMPA-CARD randomized controlled trial

“…A growing body of evidence have identified the antioxidant properties of empagliflozin [ 5 ]. In vivo experiments have shown that empagliflozin plays a cardioprotective role by impeding inflammatory responses and myocardial fibrosis in human hearts, and therefore, prevents the progression of diabetic cardiomyopathy [ 6 ].…”