Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor Ameliorate Metabolic Disorder and Obesity Induced Cardiomyocyte Injury and Mitochondrial Remodeling

• Published in: International journal of molecular sciences Vol. 24; no. 7; p. 6842
• Main Authors: Jhuo, Shih-Jie, Lin, Yi-Hsiung, Liu, I-Hsin, Lin, Tsung-Hsien, Wu, Bin-Nan, Lee, Kun-Tai, Lai, Wen-Ter
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.04.2023; MDPI
• Subjects: Animals; Arrhythmia; Benzhydryl Compounds - metabolism; Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Biosynthesis; Biotechnology industry; Ca2+-transporting ATPase; Calcium (mitochondrial); Calcium ions; calcium overload; Cardiac arrhythmia; Cardiac patients; Cardiomyocytes; Cardiotoxicity; Congestive heart failure; Dextrose; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; empagliflozin; epicardial fat; Gene expression; Glibenclamide; Glucose; Glucose transporter; Heart; Heart failure; Heart Failure - metabolism; High fat diet; Homeostasis; Metabolic disorders; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria, Heart - metabolism; Myocytes, Cardiac - metabolism; Obesity; Obesity - complications; Obesity - drug therapy; Obesity - metabolism; Overloading; Oxidative stress; Protein expression; Proteins; Reactive Oxygen Species - metabolism; Resveratrol; Secretome; SGLT2 inhibitor; SIRT1 protein; Sodium; Sodium-Glucose Transporter 2 - metabolism; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Superoxide dismutase; Type 2 diabetes; United States; Taiwan; empagliflozin; calcium overload; epicardial fat; SGLT2 inhibitor; mitochondria; oxidative stress
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076842

Sodium-glucose transporter 2 inhibitors (SGLT2is) exert significant cardiovascular and heart failure benefits in type 2 diabetes mellitus (DM) patients and can help reduce cardiac arrhythmia incidence in clinical practice. However, its effect on regulating cardiomyocyte mitochondria remain unclear. To evaluate its effect on myocardial mitochondria, C57BL/6J mice were divided into four groups, including: (1) control, (2) high fat diet (HFD)-induced metabolic disorder and obesity (MDO), (3) MDO with empagliflozin (EMPA) treatment, and (4) MDO with glibenclamide (GLI) treatment. All mice were sacrificed after 16 weeks of feeding and the epicardial fat secretome was collected. H9c2 cells were treated with the different secretomes for 18 h. ROS production, Ca distribution, and associated proteins expression in mitochondria were investigated to reveal the underlying mechanisms of SGLT2is on cardiomyocytes. We found that lipotoxicity, mitochondrial ROS production, mitochondrial Ca overload, and the levels of the associated protein, SOD1, were significantly lower in the EMPA group than in the MDO group, accompanied with increased ATP production in the EMPA-treated group. The expression of mfn2, SIRT1, and SERCA were also found to be lower after EMPA-secretome treatment. EMPA-induced epicardial fat secretome in mice preserved a better cardiomyocyte mitochondrial biogenesis function than the MDO group. In addition to reducing ROS production in mitochondria, it also ameliorated mitochondrial Ca overload caused by MDO-secretome. These findings provide evidence and potential mechanisms for the benefit of SGLT2i in heart failure and arrhythmias.