Man-Chen Hsu, Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
Ru-Wen Chang, Cardiovascular Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
Mu-Chun Wang, Department of Cardiovascular Surgery, Min-Sheng General Hospital, Taoyuan, Taiwan.
Chia-Hui Chen, Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
Wen-Hua Chen, Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
Tzong-Shyuan Lee, Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei, TaiwanFollow
Chih-Hsien Wang, Cardiovascular Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, TaiwanFollow

AMP-activated protein kinase, Diabetic cardiomyopathy, Empagliflozin, Sodi-um-glucose cotransporter two inhibitors, Transcription factor EB

The highly selective SGLT2 inhibitor (SGLT2i) is reported to have beneficial effects on diabetic cardiac hypertrophy; however, the molecular mechanisms underlying the cardioprotection of SGLT2i are not fully understood. In this study, we investigated the impact of the SGLT2 Inhibitor empagliflozin (EMPA) on diabetic hearts and its regulatory mechanisms in high-fat-diet (HFD)- and streptozotocin (STZ)-treated rats. Male rats orally administered HFD/STZ treatment for eight weeks, with or without EMPA (10 mg/kg), were used as our in vivo model. Hematoxylin and eosin (H&E) staining was used for histological examination. Western blot analysis and immunohistochemistry were used to analyze the expression of proteins. Daily EMPA administration prevented the HFD/STZ treatment-induced cardiac hypertrophy by activating the AMP-activated protein kinase (AMPK)/transcription factor EB (TFEB)-mediated upregulation of autophagy- and antioxidant-related proteins. Moreover, EMPA treatment decreased oxidative stress by increasing the antioxidant capacity and protein expression of antioxidant proteins while downregulating the levels of 4- hydroxy-2E-nonenal in the hearts of diabetic rats. Furthermore, EMPA treatment decreased cardiomyocyte apoptosis and increased heart mitochondrial function. The AMPK/TFEB signaling-mediated increase in autophagy, antioxidant capacity, mitochondrial function, and attenuated cardiomyocyte apoptosis may be crucial in the anti-hypertrophic effect conferred by SGLT2i. Our clinical implications suggest a novel pharmacological approach for treating diabetic cardiomyopathy by modulating autophagy and redox homeostasis.

Hsu, Man-Chen; Chang, Ru-Wen; Wang, Mu-Chun; Chen, Chia-Hui; Chen, Wen-Hua; Lee, Tzong-Shyuan; and Wang, Chih-Hsien (2025) "Selective sodium-glucose cotransporter two inhibitor empagliflozin ameliorates diabetic cardiomyopathy by activating the AMPK/TFEB signaling pathway.," Journal of Food and Drug Analysis: Vol. 33 : Iss. 4 , Article 6.
Available at: https://doi.org/10.38212/2224-6614.3563

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