Canagliflozin mitigates ferroptosis and ameliorates heart failure in rats with preserved ejection fraction

Recently, hypoglycemic drugs belonging to sodium-glucose cotransporter 2 inhibitors (SGLT2i) have generated significant interest due to their clear cardiovascular benefits for heart failure with preserved ejection fraction (HFpEF) since there are no effective drugs that may improve clinical outcomes...

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Published in:Naunyn-Schmiedeberg's archives of pharmacology 2022-08, Vol.395 (8), p.945-962
Main Authors: Ma, Sai, He, Li-Li, Zhang, Guo-Rui, Zuo, Qing-Juan, Wang, Zhong-Li, Zhai, Jian-Long, Zhang, Ting-Ting, Wang, Yan, Ma, Hui-Juan, Guo, Yi-Fang
Format: Article
Language:English
Subjects:
Antidiabetics
Apoptosis
Biomedical and Life Sciences
Biomedicine
Cell death
Congestive heart failure
Ejection fraction
Ferritin
Ferroptosis
Glutathione peroxidase
Heart failure
Iron
Lipid peroxidation
Neurosciences
Original
Original Article
Pharmacology/Toxicology
Proteomics
Sodium-glucose cotransporter
Transferrins
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Summary:Recently, hypoglycemic drugs belonging to sodium-glucose cotransporter 2 inhibitors (SGLT2i) have generated significant interest due to their clear cardiovascular benefits for heart failure with preserved ejection fraction (HFpEF) since there are no effective drugs that may improve clinical outcomes for these patients over a prolonged period. But, the underlying mechanisms remain unclear, particularly its effects on ferroptosis, a newly defined mechanism of iron-dependent non-apoptotic cell death during heart failure (HF). Here, with proteomics, we demonstrated that ferroptosis might be a key mechanism in a rat model of high-salt diet-induced HFpEF, characterized by iron overloading and lipid peroxidation, which was blocked following treatment with canagliflozin. Data are available via ProteomeXchange with identifier PXD029031. The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4, glutathione peroxidase 4, ferritin heavy chain 1, transferrin receptor, Ferroportin 1, iron, glutathione, malondialdehyde, and 4-hydroxy-trans-2-nonenal. These findings highlight the fact that targeting ferroptosis may serve as a cardioprotective strategy for HFpEF prevention and suggest that canagliflozin may exert its cardiovascular benefits partly via its mitigation of ferroptosis.
ISSN:0028-1298
1432-1912
DOI:10.1007/s00210-022-02243-1