Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway

Pengbo Sun; Yangyang Wang; Yipei Ding; Jingyi Luo; Jin Zhong; Naihan Xu; Yaou Zhang; Weidong Xie

doi:10.1016/j.isci.2021.102521

Canagliflozin attenuates lipotoxicity in cardiomyocytes and protects diabetic mouse hearts by inhibiting the mTOR/HIF-1α pathway

iScience. 2021 May 7;24(6):102521. doi: 10.1016/j.isci.2021.102521. eCollection 2021 Jun 25.

Authors

Pengbo Sun^{1

2

3}, Yangyang Wang^{1

2

3}, Yipei Ding^{2

3}, Jingyi Luo^{2

3}, Jin Zhong^{1

2

3}, Naihan Xu^{1

2

3}, Yaou Zhang^{1

2

3}, Weidong Xie^{1

2

3}

Affiliations

¹ Open FIESTA Center, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
² State Key Laboratory of Chemical Oncogenomic, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
³ Key Lab in Health Science and Technology, Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.

Abstract

Lipotoxicity plays an important role in the development of diabetic heart failure (HF). Canagliflozin (CAN), a marketed sodium-glucose co-transporter 2 inhibitor, has significantly beneficial effects on HF. In this study, we evaluated the protective effects and mechanism of CAN in the hearts of C57BL/6J mice induced by high-fat diet/streptozotocin (HFD/STZ) for 12 weeks in vivo and in HL-1 cells (a type of mouse cardiomyocyte line) induced by palmitic acid (PA) in vitro. The results showed that CAN significantly ameliorated heart functions and inflammatory responses in the hearts of the HFD/STZ-induced diabetic mice. CAN significantly attenuated the inflammatory injury induced by PA in the HL-1 cells. Furthermore, CAN seemed to bind to the mammalian target of rapamycin (mTOR) and then inhibit mTOR phosphorylation and hypoxia-inducible factor-1α (HIF-1α) expression. These results indicated that CAN might attenuate lipotoxicity in cardiomyocytes by inhibiting the mTOR/HIF-1α pathway and then show protective effects on diabetic hearts.

Keywords: Human metabolism; Molecular biology.