Canagliflozin Attenuates Lipotoxicity in Cardiomyocytes by Inhibiting Inflammation and Ferroptosis through Activating AMPK Pathway

被引:51
|
作者
Zhang, Wanqiu [1 ,2 ]
Lu, Jinghua [1 ,2 ]
Wang, Yangyang [1 ,2 ,3 ]
Sun, Pengbo [1 ,2 ,3 ]
Gao, Tong [1 ,2 ]
Xu, Naihan [1 ,2 ,3 ]
Zhang, Yaou [1 ,2 ,3 ]
Xie, Weidong [1 ,2 ,3 ]
机构
[1] Tsinghua Univ, Shenzhen Int Grad Sch, State Key Lab Chem Oncogen, Shenzhen 518055, Peoples R China
[2] Tsinghua Univ, Inst Biopharmaceut & Hlth Engn, Shenzhen Int Grad Sch, Key Lab Hlth Sci & Technol, Shenzhen 518055, Peoples R China
[3] Tsinghua Univ, Open FIESTA Ctr, Shenzhen Int Grad Sch, Shenzhen 518055, Peoples R China
关键词
canagliflozin; lipotoxicity; cardiomyocytes; inflammation; ferroptosis; AMPK; CARDIOMYOPATHY;
D O I
10.3390/ijms24010858
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Diabetic cardiomyopathy (DCM) is a myocardial disease independent of other cardiovascular diseases, such as coronary heart disease, hypertension, etc. Lipotoxicity is closely related to DCM. In this study, we investigated the mechanism of lipid metabolism disturbance in DCM in HL-1 cells. Through bioinformatics and Western blotting analysis, we found that canagliflozin (CAN) significantly inhibited the expression of inflammatory factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Ferroptosis is mediated by lipid peroxidation. We demonstrated the presence of ferroptosis in cardiomyocytes by detecting intracellular Fe2+ content and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH), and mitochondrial membrane potential (MMP). CAN could significantly regulate the indicators of ferroptosis. By using specific inhibitors celecoxib (coxib), S-methylisothiourea sulfate (SMT), Ferrostatin-1 (Fer-1), and Compound C, we further found that CAN regulated inflammation and ferroptosis through AMP-activated protein (AMPK), and inflammation interacted with ferroptosis. Our study indicated that CAN attenuated lipotoxicity in cardiomyocytes by regulating inflammation and ferroptosis through activating the AMPK pathway. This study provides a new direction of myocardial lipotoxicity and some new information for the treatment of DCM.
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页数:14
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