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Updated: Jun 7, 2026
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Canagliflozin ameliorates ferritinophagy in HFpEF rats
Sai Ma1, Qing-Juan Zuo2, Li-Li He2
1Department of Internal Medicine, Hebei General Hospital, Shijiazhuang, Hebei, China.
Background:
Recent studies have shown that sodium-glucose cotransporters-2 (SGLT2) inhibitors significantly improve major adverse cardiovascular events in heart failure with preserved ejection fraction (HFpEF) patients, but the exact mechanism is unknown. Ferritinophagy is a special form of selective autophagy that participates in ferroptosis. In this study, we aimed to investigate whether ferritinophagy was activated during the occurrence of HFpEF, and whether canagliflozin (CANA) could inhibite ferritinophagy.
Methods:
We reared Dahl salt-sensitive (DSS) rats on a high-salt diet to construct a hypertensive HFpEF model, and simultaneously administered CANA intervention. Then we detected indicators related to ferritinophagy.
Results:
The expression of nuclear receptor coactivator 4 (NCOA4), as well as microtubule-associated proteins light chain 3 (LC3), Bcl-2 interacting protein 1 (Beclin-1) and p62, were upregulated in HFpEF rats, accompanied by the downregulation of ferritin heavy chain 1 (FTH1), upregulation of mitochondrial iron transporter sideroflexin1 (SFXN1) and increased reactive oxygen species (ROS) production. Above changes were diminished by CANA.
Conclusion:
Ferritinophagy is activated in HFpEF rats and then inhibited by CANA, leading to HFpEF benefits. The inhibition of ferritinophagy could provide new prospective targets for the prevention and treatment of HFpEF, and provide new ideas for investigating the mechanism of cardiovascular benefit of SGLT2 inhibitors.
Insights
Sodium-glucose cotransporter-2 (SGLT2) inhibitors like canagliflozin may benefit heart failure with preserved ejection fraction (HFpEF) by inhibiting ferritinophagy. This study shows ferritinophagy activation in HFpEF rats, which canagliflozin reversed.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Metabolic Disease
Background:
- Sodium-glucose cotransporter-2 (SGLT2) inhibitors show cardiovascular benefits in heart failure with preserved ejection fraction (HFpEF).
- The precise mechanisms underlying these benefits, particularly concerning cellular processes like ferritinophagy, remain unclear.
- Ferritinophagy, a selective autophagy pathway involved in ferroptosis, is explored as a potential mediator.
Purpose of the Study:
- To investigate the role of ferritinophagy in the development of HFpEF.
- To determine if canagliflozin (CANA), an SGLT2 inhibitor, can inhibit ferritinophagy in a HFpEF model.
Main Methods:
- A rat model of hypertensive HFpEF was established using Dahl salt-sensitive (DSS) rats on a high-salt diet.
- Simultaneous intervention with canagliflozin (CANA) was administered.
- Key indicators of ferritinophagy, ferroptosis, and oxidative stress were assessed.
Main Results:
- HFpEF rats exhibited upregulated markers of ferritinophagy (NCOA4, LC3, Beclin-1, p62) and ferroptosis (downregulated FTH1, upregulated SFXN1).
- Increased reactive oxygen species (ROS) production was observed in HFpEF rats.
- Canagliflozin (CANA) treatment reversed these molecular changes, diminishing ferritinophagy and oxidative stress.
Conclusions:
- Ferritinophagy is activated in the HFpEF condition and is subsequently inhibited by canagliflozin (CANA), contributing to HFpEF benefits.
- Inhibition of ferritinophagy presents a potential therapeutic target for HFpEF prevention and treatment.
- This study offers novel insights into the cardiovascular protective mechanisms of SGLT2 inhibitors.
