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Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKα/TGF‐β/Smad signalling in type 2 diabetic rats

Tian, Jingjing ; Zhang, Mingjun ; Suo, Mengying ; Liu, Dian ; Wang, Xuyang ; Liu, Ming ; Pan, Jinyu ; Jin, Tao ; An, Fengshuang

Journal of cellular and molecular medicine, 2021-08, Vol.25 (16), p.7642-7659 [Periódico revisado por pares]

England: John Wiley & Sons, Inc

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Título:
Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKα/TGF‐β/Smad signalling in type 2 diabetic rats
Autor: Tian, Jingjing ; Zhang, Mingjun ; Suo, Mengying ; Liu, Dian ; Wang, Xuyang ; Liu, Ming ; Pan, Jinyu ; Jin, Tao ; An, Fengshuang
Assuntos: AMP-Activated Protein Kinases - metabolism ; Animals ; Antibodies ; Antidiabetics ; Benzhydryl Compounds - pharmacology ; cardiac fibroblast ; cardiac fibrosis ; Cardiac function ; Cardiomyocytes ; Cardiomyopathy ; Cardiovascular disease ; Clinical trials ; Collagen ; Congestive heart failure ; dapagliflozin ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - complications ; Diabetes Mellitus, Experimental - drug therapy ; Diabetes Mellitus, Experimental - physiopathology ; Diabetes Mellitus, Type 2 - complications ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - physiopathology ; Diabetic Cardiomyopathies - drug therapy ; Diabetic Cardiomyopathies - etiology ; Diabetic Cardiomyopathies - pathology ; diabetic cardiomyopathy ; Diet, High-Fat ; Disease Models, Animal ; endothelial‐to‐mesenchymal transition ; Epithelial-Mesenchymal Transition ; Fibroblasts ; Fibroblasts - metabolism ; Fibroblasts - pathology ; Fibrosis ; Fibrosis - drug therapy ; Fibrosis - etiology ; Fibrosis - pathology ; Glucose ; Glucosides - pharmacology ; Heart failure ; Hyperglycemia ; Laboratory animals ; Male ; Mesenchyme ; Mesoderm - metabolism ; Mesoderm - pathology ; Metabolism ; Metformin ; Microscopy ; Mortality ; Original ; Oxidative stress ; Pathogenesis ; Rats ; SGLT2 inhibitor ; Signal Transduction ; siRNA ; Smad protein ; Smad4 Protein - metabolism ; Sodium-glucose cotransporter ; Sodium-Glucose Transporter 2 Inhibitors - pharmacology ; Streptozocin ; Transforming Growth Factor beta - metabolism ; Transforming growth factor-b
É parte de: Journal of cellular and molecular medicine, 2021-08, Vol.25 (16), p.7642-7659
Notas: Funding information
This project was supported by the National Natural Science Foundation of China (No. 81670325) and (No. 81970368) and the Key Research and Development Project of Shandong Provence (No. 2019GSF108124)
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Descrição: Diabetic cardiomyopathy (DCM) is one of the leading causes of heart failure in patients with diabetes mellitus, with limited effective treatments. The cardioprotective effects of sodium‐glucose cotransporter 2(SGLT2) inhibitors have been supported by amounts of clinical trials, which largely fills the gap. However, the underlying mechanism still needs to be further explored, especially in terms of its protection against cardiac fibrosis, a crucial pathophysiological process during the development of DCM. Besides, endothelial‐to‐mesenchymal transition (EndMT) has been reported to play a pivotal role in fibroblast multiplication and cardiac fibrosis. This study aimed to evaluate the effect of SGLT2 inhibitor dapagliflozin (DAPA) on DCM especially for cardiac fibrosis and explore the underlying mechanism. In vivo, the model of type 2 diabetic rats was built with high‐fat feeding and streptozotocin injection. Untreated diabetic rats showed cardiac dysfunction, increased myocardial fibrosis and EndMT, which was attenuated after treatment with DAPA and metformin. In vitro, HUVECs and primary cardiac fibroblasts were treated with DAPA and exposed to high glucose (HG). HG‐induced EndMT in HUVECs and collagen secretion of fibroblasts were markedly inhibited by DAPA. Up‐regulation of TGF‐β/Smad signalling and activity inhibition of AMPKα were also reversed by DAPA treatment. Then, AMPKα siRNA and compound C abrogated the anti‐EndMT effects of DAPA in HUVECs. From above all, our study implied that DAPA can protect against DCM and myocardial fibrosis through suppressing fibroblast activation and EndMT via AMPKα‐mediated inhibition of TGF‐β/Smad signalling.
Editor: England: John Wiley & Sons, Inc
Idioma: Inglês

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Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKα/TGF‐β/Smad signalling in type 2 diabetic rats

Tian, Jingjing ; Zhang, Mingjun ; Suo, Mengying ; Liu, Dian ; Wang, Xuyang ; Liu, Ming ; Pan, Jinyu ; Jin, Tao ; An, Fengshuang

England: John Wiley & Sons, Inc

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