Canagliflozin Regulates Ferroptosis, Potentially via Activating AMPK/PGC-1α/Nrf2 Signaling in HFpEF Rats

Aims: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been found to ameliorate major adverse cardiovascular events in patients with heart failure with preserved ejection fraction (HFpEF), but the exact mechanism is unknown. Ferroptosis is a form of programmed necrosis. Herein, we verified that canagliflozin (CANA) ameliorates heart function in HFpEF rats, partly by regulating ferroptosis, which may be activated by AMPK/PGC-1α/Nrf2 signaling. Methods: An HFpEF model was established and subjected to CANA treatment. Blood pressure was monitored, and echocardiography was performed at the 12th week. Pathological examination was performed, and expression of ferroptosis-associated proteins and AMPK/PGC-1α/Nrf2 signaling related proteins was detected. Results: CANA had an antihypertensive effect and increased E/A ratios in HFpEF rats. Myocardial pathology was ameliorated, on the basis of decreased cross-sectional area and intercellular fibrosis. Acyl-CoA synthetase long-chain family member 4 (ACSL4) expression increased, whereas ferritin heavy chain 1 (FTH1) expression decreased in HFpEF rats, which showed iron overload. CANA reversed changes in ACSL4 and FTH1, and decreased iron accumulation, but did not alter glutathione peroxidase 4 (GPX4) expression. The expression of AMPK/PGC-1α/Nrf2 signaling related proteins and heme oxygenase 1 (HO-1) in the HFpEF group decreased but was reverted after CANA treatment. Conclusions: CANA regulates ferroptosis, potentially via activating AMPK/PGC-1α/Nrf2 signaling in HFpEF rats.