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

Int J Mol Sci. 2023 Jan 3;24(1):858. doi: 10.3390/ijms24010858.

Abstract

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.

Keywords: AMPK; canagliflozin; cardiomyocytes; ferroptosis; inflammation; lipotoxicity.

MeSH terms

  • AMP-Activated Protein Kinases
  • Canagliflozin* / therapeutic use
  • Diabetic Cardiomyopathies* / drug therapy
  • Ferroptosis* / drug effects
  • Humans
  • Inflammation / drug therapy
  • Lipid Peroxidation*
  • Myocytes, Cardiac
  • Reactive Oxygen Species
  • Sodium-Glucose Transporter 2 Inhibitors* / pharmacology
  • Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

  • AMP-Activated Protein Kinases
  • Canagliflozin
  • Reactive Oxygen Species
  • Sodium-Glucose Transporter 2 Inhibitors

Grants and funding

The present study was supported by the Shenzhen Science and Technology Program (Grant Nos. WDZC20200820150804001, JSGG20200519160752002, RCJC20200714114433069, JCYJ20200109142818589) and funding by the State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University (2021C02-15).