Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress

Ren, Fangfang; Xie, Zuo-yi; Jiang, Yongchao; Guan, Xuan; Chen, Qiaoying; Lai, Teng-Fang; Li, Lei

doi:10.1038/s41401-021-00805-2

Cited by 43 publications

(28 citation statements)

References 36 publications

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“…Dapagliflozin has been proven in studies to alleviate glucotoxicity by lowering excessive glucose influx into renal tubular epithelial cells under high glucose circumstances through activating GAPDH ( 64 ). Furthermore, dapagliflozin alleviates pressure overload-induced myocardial remodeling in mice via inhibiting ER stress-mediated apoptosis ( 65 ). Empagliflozin improved renal ischemia/reperfusion injury in non-diabetic rats by promoting mitochondrial biogenesis and inhibiting oxidative stress and apoptosis ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

Wang

Li²,

Sun³

et al. 2022

Front. Cardiovasc. Med.

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PurposeSodium-glucose cotransporter 2 (SGLT2) inhibitors have cardiorenal protective effects regardless of whether they are combined with type 2 diabetes mellitus, but their specific pharmacological mechanisms remain undetermined.Materials and MethodsWe used databases to obtain information on the disease targets of “Chronic Kidney Disease,” “Heart Failure,” and “Type 2 Diabetes Mellitus” as well as the targets of SGLT2 inhibitors. After screening the common targets, we used Cytoscape 3.8.2 software to construct SGLT2 inhibitors' regulatory network and protein-protein interaction network. The clusterProfiler R package was used to perform gene ontology functional analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analyses on the target genes. Molecular docking was utilized to verify the relationship between SGLT2 inhibitors and core targets.ResultsSeven different SGLT2 inhibitors were found to have cardiorenal protective effects on 146 targets. The main mechanisms of action may be associated with lipid and atherosclerosis, MAPK signaling pathway, Rap1 signaling pathway, endocrine resistance, fluid shear stress, atherosclerosis, TNF signaling pathway, relaxin signaling pathway, neurotrophin signaling pathway, and AGEs-RAGE signaling pathway in diabetic complications were related. Docking of SGLT2 inhibitors with key targets such as GAPDH, MAPK3, MMP9, MAPK1, and NRAS revealed that these compounds bind to proteins spontaneously.ConclusionBased on pharmacological networks, this study elucidates the potential mechanisms of action of SGLT2 inhibitors from a systemic and holistic perspective. These key targets and pathways will provide new ideas for future studies on the pharmacological mechanisms of cardiorenal protection by SGLT2 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

Wang

Li²,

Sun³

et al. 2022

Front. Cardiovasc. Med.

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“…As previously mentioned, cardiac remodeling, caused or exacerbated by varying pathological changes, will eventually result in serious consequences, for which there are no effective drugs ( Hao et al, 2021 ; Ni et al, 2022 ; Ren et al, 2021 ). New therapeutic strategies are needed to be introduced clinically for protecting against pressure overload-induced cardiac injury ( Li X. et al, 2021 ) or targeting adverse post-MI left ventricle remodeling ( Germano et al, 2020 ).…”

Section: Disscussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…As one of the most prevalent cardiac dysfunctions, heart failure (HF) is caused by multiple cardiac diseases like coronary heart disease, hypertension, arrhythmia, and viral myocarditis ( Zhong et al, 2021 ), characterized by high morbidity and mortality ( Ren et al, 2021 ; Sokolski et al, 2022 ). A significant pathological basis of HF is cardiac remodeling, which is thought to play a key part in the clinical outcomes of heart diseases ( Liu et al, 2021 ) and occurs through various complex mechanisms, leading to changes such as pathological cardiac hypertrophy, interstitial fibrosis, increased degradation of the myocardial extracellular matrix, impaired heart functions, and even HF ( Hao et al, 2021 ; Ni et al, 2022 ; Ren et al, 2021 ). Cardiac remodeling in HF is typically characterized by myocardial hypertrophy ( Zhong et al, 2021 ), which is initially an adaptive and compensatory response to maintain the ejection fraction under increased pressure load, while irreversible damage could be induced if pathological overload persists, along with inflammatory responses, vascular dysfunction, increased extracellular matrix deposition, myocardial fibrosis, and all pathologic changes resulting in cardiac dysfunction ( Nemska et al, 2021 ; Tsuda, 2021 ; Zhong et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Qiliqiangxin Modulates the Gut Microbiota and NLRP3 Inflammasome to Protect Against Ventricular Remodeling in Heart Failure

Xiang

Xin

et al. 2022

Front. Pharmacol.

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Aims: Pathological left ventricular (LV) remodeling induced by multiple causes often triggers fatal cardiac dysfunction, heart failure (HF), and even cardiac death. This study is aimed to investigate whether qiliqiangxin (QL) could improve LV remodeling and protect against HF via modulating gut microbiota and inhibiting nod-like receptor pyrin domain 3 (NLRP3) inflammasome activation.Methods: Rats were respectively treated with QL (100 mg/kg/day) or valsartan (1.6 mg/kg/day) by oral gavage after transverse aortic constriction or sham surgery for 13 weeks. Cardiac functions and myocardial fibrosis were assessed. In addition, gut microbial composition was assessed by 16S rDNA sequencing. Furthermore, rats’ hearts were harvested for histopathological and molecular analyses including immunohistochemistry, immunofluorescence, terminal-deoxynucleotidyl transferase-mediated 2’-deoxyuridine 5’-triphosphated nick end labeling, and Western blot.Key findings: QL treatment preserved cardiac functions including LV ejection fractions and fractional shortening and markedly improved the LV remodeling. Moreover, HF was related to the gut microbial community reorganization like a reduction in Lactobacillus, while QL reversed it. Additionally, the protein expression levels like IL-1β, TNF-α, NF-κB, and NLRP3 were decreased in the QL treatment group compared to the model one.Conclusion: QL ameliorates ventricular remodeling to some extent in rats with HF by modulating the gut microbiota and NLRP3 inflammasome, which indicates the potential therapeutic effects of QL on those who suffer from HF.

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“…Dapagliflozin improves myocardial systolic function, and inhibits myocardial fibrosis and apoptosis in TAC mice [45]. By activating SIRT1 in Ang II-treated cardiomyocytes, dapagliflozin blocks the development of HF in vivo by inhibiting the perk-eIF2 α-CHOP axis of endoplasmic reticulum (ER) stress response [46]. Dapagliflozin mediates M2 polarization through a RONS-dependent STAT3-mediated pathway, reducing fibroblast infiltration during post-infarction remodeling [47].…”

Section: Direct Effect Of Dapagliflozin On the Heartmentioning

confidence: 99%

A study on the beneficial evidence and mechanism of the therapeutic effect of dapagliflozin on heart failure

Xie

Yao

2022

CDS

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Heart failure (HF) is the final manifestation of various cardiovascular (CV) diseases, which has caused a huge health burden. Although great progress has been made in the treatment strategy, it still cannot solve the dilemma of HF treatment. As a sodium glucose transporter 2 inhibitor, dapagliflozin is a hypoglycemic drug. However, recent research has found that it can play a crucial role in preventing HF, regardless of whether patients have diabetes or not. There are many mechanisms involved, so this review focuses on elucidating the beneficial evidence and mechanism of dapagliflozin in treating HF, in order to provide new insights into the treatment of HF.

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Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress

Cited by 43 publications

References 36 publications

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

Qiliqiangxin Modulates the Gut Microbiota and NLRP3 Inflammasome to Protect Against Ventricular Remodeling in Heart Failure

A study on the beneficial evidence and mechanism of the therapeutic effect of dapagliflozin on heart failure

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