The Sodium-Glucose Co-Transporter 2 Inhibitor, Empagliflozin, Protects against Diabetic Cardiomyopathy by Inhibition of the Endoplasmic Reticulum Stress Pathway

Zhou, Yang; Wu, Wei

doi:10.1159/000475942

Cited by 56 publications

(53 citation statements)

References 44 publications

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“…Recently, a large number of clinical trials have reported that empagliflozin application improved cardiovascular outcomes in diabetic patients [16,32,33]. Numerous experimental studies on diabetic animals show that empagliflozin predominantly delayed the progression of cardiomyopathy [18,24,25]. In the present study, water intake, urine volume and UGE were significantly enhanced, and the blood glucose and body weight were decreased by empagliflozin, which is consistent with the results of other studies [18,22,23,34].…”

Section: Discussionsupporting

confidence: 92%

“…In our study, excessive oxidative stress in diabetes was accompanied by elevated level of apoptosis. Not surprisingly, empagliflozin also alleviated the level of cardiomyocyte apoptosis in diabetic mice, which is also concordant with data from recent publications emphasizing the anti-apoptotic role of EMPA in hearts [24]. Empagliflozin rescues diabetic myocardial microvascular injury via the inhibition of mitochondrial fission [20].…”

Section: Discussionsupporting

confidence: 89%

“…Recent studies described the beneficial effects of empagliflozin on diastolic dysfunction in ob/ob and db/db mice [18,19], myocardial microvascular injury in streptozotocin-induced diabetic mice [20], atherosclerosis in ApoE −/− mice [21], cardiac injury in prediabetic rats [22] or myocardial infarction in animals fed with Western diet [23]. Other studies have also proved that empagliflozin protects against DCM by blocking endoplasmic reticulum stress and ameliorating cardiac interstitial fibrosis and oxidative stress [24,25]. However, little information is available about the action of empagliflozin on cardiac function in DCM via sGC-cGMP-PKG pathway.…”

Section: Introductionmentioning

confidence: 99%

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Empagliflozin prevents cardiomyopathy via sGC-cGMP-PKG pathway in type 2 diabetes mice

Xue

Wang

et al. 2019

Clinical Science

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Cardiovascular complications contribute to the major mortality and morbidity in type 2 diabetes. Diabetic cardiomyopathy (DCM) is increasingly recognized as an important cause of heart failure. EMPA-REG OUTCOME trial has reported that empagliflozin, the sodium-glucose cotransporter 2 inhibitor, exerts cardiovascular benefits on diabetic population. However, the mechanism by which empagliflozin alleviates DCM still remains unclear. In the current study, we investigated the cardiac protective effects of empagliflozin on spontaneous type 2 diabetic db/db mice and its potential mechanism. Eight weeks of empagliflozin treatment (10 mg/kg/day) decreased body weight and blood glucose level, and increased urinary glucose excretion (UGE) in diabetic mice. Echocardiography revealed that both systolic and diastolic functions of db/db mice were also obviously improved by empagliflozin. Furthermore, empagliflozin-treated diabetic mice presented with amelioration of cardiac hypertrophy and fibrosis. In addition, diabetic hearts exhibited the deterioration of oxidative stress, apoptosis and pyroptosis, while these effects were significantly counteracted after empagliflozin treatment. Moreover, empagliflozin rescued diabetes-induced suppression of sGC (soluble guanylate cyclase enzyme)-cGMP (cyclic guanosine monophosphate)-PKG (cGMP-dependent protein kinase) pathway. However, when sGC-β expression of hearts was inhibited by transvascular delivery of small interfering RNA, cardiac dysfunction was aggravated and the advantages of empagliflozin were reversed through inhibiting sGC-cGMP-PKG pathway. Collectively, these findings indicate that empagliflozin improves cardiac function involving the inhibition of oxidative stress-induced injury via sGC-cGMP-PKG pathway and may be a promising therapeutic option for DCM.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Empagliflozin prevents cardiomyopathy via sGC-cGMP-PKG pathway in type 2 diabetes mice

Xue

Wang

et al. 2019

Clinical Science

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“…The cardiovascular protection is suggested to be another drug class effect [3]. Potential mechanisms of cardiac protection with SGLT2i include renin-angiotensin system inhibition following decreased total body sodium content, reduced myocardial cytoplasmic sodium and calcium load, anti-apoptotic, anti-inflammatory, anti-oxidant effects, rescue of diabetes myocardial microvascular injuries, and reduced sympathetic overactivity, inactivation of endoplasmic reticulum stress [6,12,[38][39][40][41][42]. In this study, empagliflozin restored upregulation of PPARα and ACADM in SHR fed with high fat diet, reflecting a shift toward beneficial metabolic utilization in lipids oxidation.…”

Section: Discussionmentioning

confidence: 99%

The sodium–glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats

Lee

Shiou

Jhuo

et al. 2019

Cardiovasc Diabetol

148

113

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Background: Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure. Methods and results: The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin. Conclusions: Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.

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“…Increasing evidence indicates that dysfunction of mitochondrial energy metabolism plays a crucial role in the pathogenesis of DCM [9]. Mitochondrial uncoupling may represent one mechanism alongside increased oxidative stress and ROS production, that leads to reduced cardiac efficiency and lower ATP generation in diabetic hearts [28][29][30]. In addition, defective energy metabolism in the heart is likely to impair energy-requiring processes such as protein synthesis, maintenance of transmembrane [31].…”

Section: Discussionmentioning

confidence: 99%

Identification of Energy Metabolism Changes in Diabetic Cardiomyopathy Rats Using a Metabonomic Approach

Zhao

Dong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes. It is therefore crucial to elucidate the characteristic metabolic changes that occur during the development of diabetes to gain an understanding the pathogenesis of this disease and identify potential drug targets involved. Methods: ¹H nuclear magnetic resonance-based metabonomics combined with HPLC measurements were used to determine the metabolic changes in isolated cardiac tissues after 5 weeks, 9 weeks, and 15 weeks in rats treated with streptozotocin. Results: Pattern recognition analysis clearly discriminated the diabetic rats from time-matched control rats, suggesting that the metabolic profile of the diabetic group was markedly different from that of the controls. Quantitative analysis showed that the levels of energy metabolites, such as the high-energy phosphate pool (ATP and creatine), significantly decreased in a time-dependent manner. Correlation analysis revealed the inhibition of glycolysis and the tricarboxylic acid (TCA) cycle, enhanced lipid metabolism, and changes in some amino acids, which may have led to the decline in energy production in the DCM rats. Conclusions: The results indicated that the administration of energy substances or the manipulation of myocardial energy synthesis induced by increased glucose oxidation may contribute to the amelioration of cardiac dysfunction in diabetes.

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The Sodium-Glucose Co-Transporter 2 Inhibitor, Empagliflozin, Protects against Diabetic Cardiomyopathy by Inhibition of the Endoplasmic Reticulum Stress Pathway

Cited by 56 publications

References 44 publications

Empagliflozin prevents cardiomyopathy via sGC-cGMP-PKG pathway in type 2 diabetes mice

Empagliflozin prevents cardiomyopathy via sGC-cGMP-PKG pathway in type 2 diabetes mice

The sodium–glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats

Identification of Energy Metabolism Changes in Diabetic Cardiomyopathy Rats Using a Metabonomic Approach

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