A SGLT2 Inhibitor Dapagliflozin Alleviates Diabetic Cardiomyopathy by Suppressing High Glucose-Induced Oxidative Stress in vivo and in vitro

Xing, Yujie; Liu, Biaohu; Wan, Shujun; Cheng, Yi; Zhou, Simin; Sun, Yue; Yao, Xin-ming; Hua, Qiang; Meng, Xiang-jian; Cheng, Jinhan; Zhong, Min; Zhang, Yan; Lv, Kun; Kong, Xiang

doi:10.3389/fphar.2021.708177

“…Dapagliflozin has a variety of mechanisms to protect cardiomyocytes. By inhibiting the oxidative stress mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, it obviously ameliorated the cardiac dysfunction, improved myocardial fibrosis, apoptosis, and oxidase stress in vivo, and reduced the enhanced level of reactive oxygen species and cell death of H9c2 cells [ 23 ]. Besides, the dapagliflozin can improve the biochemical indexes related to cardiac function, including malondialdehyde (MDA), glutathione (GSH), and catalase (CAT), proinflammatory mediators (NF- κ B and tumor necrosis factor- α (TNF- α )), and apoptotic effectors (caspase-3).…”

Section: Discussionmentioning

confidence: 99%

Dapagliflozin Improves Diabetic Cardiomyopathy by Modulating the Akt/mTOR Signaling Pathway

Ren

¹

,

Pan

²

,

Zha

³

et al. 2022

BioMed Research International

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Background. Dapagliflozin can significantly improve heart failure, and Cx43 is one of the molecular mechanisms of heart failure. This study investigated the effect of dapagliflozin on Cx43 and Akt/mTOR signaling pathway in ventricular myocytes. Methods. A rat model of type 2 diabetes mellitus was established by high-fat diet combined with streptozotocin, and the animals were treated randomly with dapagliflozin. The morphological changes of the myocardium were observed by hematoxylin eosin staining, and the expression and distribution of Cx43 in ventricular myocytes were detected by immunohistochemistry. And Western blot determined the expressions of Cx43, Akt, mTOR, p62, and LC3 proteins in rat myocardium. Results. Compared with the normal control group, the heart rate of diabetic rats decreased significantly ( p < 0.05 ), QRS wave of ECG widened, and QT interval prolonged ( p < 0.05 ). Dapagliflozin treatment in diabetic rats resulted in improvements in these ECG indexes ( p < 0.05 ) with early administration group obtaining greater efficacy than the late administration group ( p < 0.05 ). In the normal control group, the cardiomyocytes were arranged orderly, and the expression of Cx43 was dense, uniform, and regular, which was higher than that in the intercalated disc. In the diabetic control model group, the cardiomyocytes were enlarged and presented disorderly with detection of Cx43 in the cytoplasm. Early use of dapagliflozin better improved these myocardial tissue lesions. Of note, as diabetic rats exhibited decreased expression of Cx43, Akt, and mTOR ( p < 0.05 ), increased p62 expression ( p < 0.05 ), and decreased LC3-II/I ratio ( p < 0.05 ), administration of dapagliflozin partially reversed the expression of the above proteins ( p < 0.05 ) with greater improvement in the early administration group compared with the late administration group ( p < 0.05 ). Conclusions. Dapagliflozin increases the expression of Cx43 in cardiomyocytes of diabetic rats and thereby alleviates heart failure partly through regulating the Akt/mTOR signaling pathway.

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“…In addition, SGLT-2 inhibitors have been found to have protective effects on the heart, kidneys, and retinas ( Fitchett et al, 2016 ; Neal et al, 2017 ; Cho et al, 2018 ; Mishriky et al, 2018 ; Wiviott et al, 2019 ). Studies have shown that DAPA protects the heart and kidneys by reducing the apoptosis of cells ( Shih et al, 2021 ; Xing et al, 2021 ). Recent reports have also shown that SGLT-2 inhibitors reduced macrovascular and microvascular complications by affecting vascular remodeling ( Dziuba et al, 2014 ; Ott et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Dapagliflozin Reduces Apoptosis of Diabetic Retina and Human Retinal Microvascular Endothelial Cells Through ERK1/2/cPLA2/AA/ROS Pathway Independent of Hypoglycemic

Hu

¹

,

Qian

²

,

Li

³

et al. 2022

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Introduction: It is known that the metabolic disorder caused by high glucose is one of pathogenesis in diabetic retinopathy (DR), the leading cause of blindness, due to the main pathological change of apoptosis of endothelial cells (ECs). In previous studies, the potential impact of sodium glucose cotransporter-2 (SGLT-2), whose inhibitors slow the progression of DR, has not been elucidated. The purpose of the presented study was to explore the effect of SGLT-2 inhibitors dapagliflozin (DAPA) on apoptosis of diabetic mice retina and human retinal microvascular endothelial cells (HRMECs), examine the effects of dapagliflozin on HRMECs metabolism, and explore the molecular processes that affect DR.Methods and Results: The eyeballs of male streptozotocin (STZ)-induced diabetic C57BL/6N mice were evaluated. C57BL/6N mice were divided into control group (CON), diabetic untreated group (DM), diabetic dapagliflozin treatment group (DM + DAPA) and diabetic insulin treatment group (DM + INS). Hematoxylin-Eosin (HE) staining was performed to observe the pathological structure of the mice retina, and TUNEL staining to detect apoptosis of mice retinal cells. In vitro, DCFH-DA and western blot (WB) were used to evaluate ROS, Bcl-2, BAX, cleaved-caspase 3 in HRMECs and metabolomics detected the effect of dapagliflozin on the metabolism of HRMECs. And then, we performed correlation analysis and verification functions for significantly different metabolites. In vivo, dapagliflozin reduced the apoptosis of diabetic mice retina independently of hypoglycemic. In vitro, SGLT-2 protein was expressed on HRMECs. Dapagliflozin reduced the level of ROS caused by high glucose, decreased the expression of cleaved-caspase3 and the ratio of BAX/Bcl-2. Metabolomics results showed that dapagliflozin did not affect the intracellular glucose level. Compared with the high glucose group, dapagliflozin reduced the production of arachidonic acid (AA) and inhibited the phosphorylation of ERK1/2, therefore, reducing the phosphorylation of cPLA2, which is a key enzyme for arachidonic acid release.Conclusion: Collectively, results unearthed for the first time that dapagliflozin reduced apoptosis of retina induced by DM whether in vivo or in vitro. Dapagliflozin did not affect the glucose uptake while mitigated intracellular arachidonic acid in HRMECs. Dapagliflozin alleviated HRMECs apoptosis induced by high glucose through ERK/1/2/cPLA2/AA/ROS pathway.

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“…Both approaches significantly ameliorated oxidative stress and enhanced the antioxidant capacity in the cardiomyocytes. Dapagliflozin had a cardioprotective and antioxidant effect through attenuation of oxidative stress and enhancing the antioxidant capacity of cardiomyocytes [ 39 , 40 ]. The cardiomyocytes express the SGLT1 isoform and there is little evidence for SGLT2 expression [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…The cardiomyocytes express the SGLT1 isoform and there is little evidence for SGLT2 expression [ 30 ]. Therefore, Xing et al [ 40 ] using in vitro experiments owed the cardioprotective effect of dapagliflozin to the direct inhibition of ROS production. Additionally, it has been reported that low-intensity exercise decreases oxidative stress and upregulates the expression and function of antioxidant enzymes in cardiomyocytes [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

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Exercise Augments the Effect of SGLT2 Inhibitor Dapagliflozin on Experimentally Induced Diabetic Cardiomyopathy, Possible Underlying Mechanisms

Eldesoqui

¹

,

El-Dken

²

,

Mostafa

³

et al. 2022

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One of the most prevalent cardiovascular problems linked with type 2 diabetes mellitus (T2DM) is diabetic cardiomyopathy (DCM). DCM is associated with myocardial oxidative stress, inflammation, apoptosis, suppressed autophagy, extracellular matrix remodeling, and fibrosis. The current study aims to investigate the protective effect of sodium-glucose transport 2 inhibitor (SGLT2i) dapagliflozin and/or exercise on DCM. Thirty adult male Sprague Dawley rats are used. T2DM is induced by a 6-week high-fat diet (HFD) followed by a single intraperitoneal (IP) injection of 35 mg/kg streptozotocin (STZ). Rats are divided into five groups, control, diabetic (DM), DM + swimming, DM + dapagliflozin, and DM + dapagliflozin and swimming. Serum glucose, insulin, insulin resistance (HOMA-IR), and cardiac enzymes (CK-MB and lactate dehydrogenase (LDH) are measured. Heart specimens are used for evaluation of cellular oxidative stress markers malondialdehyde (MDA), antioxidant enzymes, glutathione (GSH), and catalase (CAT), as well as mRNA expression of TGF-β, MMP9, IL-1β, and TNF-α. Stained sections with haematoxylin and eosin (H & E) and Masson trichrome are used for histopathological evaluation and detection of fibrosis, respectively. Immunohistochemical staining for apoptosis (caspase-3), and autophagy (LC3) are also carried out. The combinations of SGLT2i and exercise exhibited the most significant cardioprotective effect. It improved diabetic-induced histopathological alterations in the myocardium and attenuated the elevation of serum blood glucose, CK-MB, LDH, myocardial MDA, and mRNA expression of TNF-α, IL-1β, TGF-β, MMP9, and the immune expression of caspase-3. Moreover, this combination increased the serum insulin, myocardial antioxidants GSH and CAT, and increase the immune expression of the LC-3. In conclusion, a combination of SGLT2i and exercise exerted a better antioxidant, anti-inflammatory, and antifibrotic effect in DCM. Moreover, the combination enhances the autophagic capacity of the heart.

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A SGLT2 Inhibitor Dapagliflozin Alleviates Diabetic Cardiomyopathy by Suppressing High Glucose-Induced Oxidative Stress in vivo and in vitro

Cited by 34 publications

References 47 publications

Dapagliflozin Improves Diabetic Cardiomyopathy by Modulating the Akt/mTOR Signaling Pathway

Dapagliflozin Improves Diabetic Cardiomyopathy by Modulating the Akt/mTOR Signaling Pathway

Dapagliflozin Reduces Apoptosis of Diabetic Retina and Human Retinal Microvascular Endothelial Cells Through ERK1/2/cPLA2/AA/ROS Pathway Independent of Hypoglycemic

Exercise Augments the Effect of SGLT2 Inhibitor Dapagliflozin on Experimentally Induced Diabetic Cardiomyopathy, Possible Underlying Mechanisms

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