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Canagliflozin regulates ferroptosis, potentially via activating AMPK/PGC-1α/Nrf2 signaling, in HFpEF rats
According to a new article in Cardiovascular Innovations and Applications, 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. In the article, the authors verified that canagliflozin (CANA) ameliorates heart function in HFpEF rats, partly by regulating ferroptosis, which may be activated by AMPK/PGC-1α/Nrf2 signaling.
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.
CANA had an antihypertensive effect and increased E/A ratios in HFpEF rats. Myocardial pathology was ameliorated, based on 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.
More information: Sai Ma et al, Canagliflozin Regulates Ferroptosis, Potentially via Activating AMPK/PGC-1α/Nrf2 Signaling in HFpEF Rats, Cardiovascular Innovations and Applications (2023). DOI: 10.15212/CVIA.2022.0024
