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

Abstract

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.

Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy

“…So further indepth study is needed. Notably, a recent study reported that Cana exert its cardiovascular benefits partly via its mitigation of ferroptosis in a rodent model of HFpEF (15), which provide a new idea for the research of SGLT2is in heart disease, even DCM. So far, the cardioprotective mechanisms of Cana on DCM are not fully clear and needs to be further studied.…”

“…(3) DCM + Cana group: DCM model mice were treated with 20 mg/kg/d canagliflozin (15,19,20) (C126191, Aladdin, China) for 6 weeks. On the last day, electrocardiogram examination was performed after the drug intervention, then all animals were weighted and sacrificed, heart tissues were removed freshly and aseptically for measurements.…”

“…At present, the protective effects of Cana on the heart have been gradually revealed in various myocardial injuries, such as autoimmune myocarditis (13), myocardial lipotoxicity (12) and even isoprenaline-induced cardiotoxicity (14). In addition, a recent study reported that Cana may exert its cardiovascular benefits partly via its mitigation of ferroptosis (15), which is similar to the effect of empagliflozin ( 16), another SGLT2i. These studies provide clues that regulating ferroptosis may play an important role in the cardioprotective effects of SGLT2is.…”

Ferroptosis: The Potential Target in Heart Failure with Preserved Ejection Fraction

“…This is a major milestone in the treatment of HFpEF, and so SGLT2i is of significant interest. Canagliflozin was shown to block ferroptosis and treat HFpEF [ 77 ], which demonstrated that the intervention of ferroptosis could be used as a new attempt. Further research is needed to clarify the causal relationship and specific mechanism between ferroptosis and HFpEF and provide an opportunity for designing new therapeutic interventions.…”

“…In addition, the expression of GPX4 and ferritin (Fth1) was significantly downregulated in a pressure overload-induced heart failure model in rats, while knockdown of TLR4 or NOX4 gene restored the expression of GPX4 and Fth1 in cardiomyocytes and improved ventricular remodeling and LV function in rats with heart failure [ 76 ]. It is worth noting that Sai Ma et al [ 77 ] demonstrated that ferroptosis might be a key mechanism in a rat model of HFpEF with proteomics, which was blocked following treatment with canagliflozin, a sodium–glucose cotransporter 2 inhibitor (SGLT2i).…”