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 longchain 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.