Calycosin protects against post-myocardial infarction heart failure by activating the NRF2/HO-1 signaling pathway.

BACKGROUND: Myocardial infarction (MI) is the most common cause of heart failure (HF). Calycosin (CAL), an active component of Radix astragali, has been reported to improve HF. However, the functional effect of CAL on the progression of post-MI HF has not been extensively clarified. This study aimed to investigate whether the cardioprotective effects of CAL are related to ferroptosis. METHODS: In vitro, an oxygen and glucose deprivation (OGD)-induced H9c2 cells was established. Ferroptosis activator erastin and nuclear factor erythroid 2-related factor 2 (NRF2) knockdown were used in rescue experiments. Reactive oxygen species (ROS), malondialdehyde (MDA) levels, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP), and Fe2+ concentration levels were measured using corresponding kits, respectively. In vivo, a left anterior descending ligation-induced HF model was used to determine the effects of CAL on HF rat hearts. Serum N-terminal pro-brain natriuretic peptide, cardiac function, pathological changes, oxidative stress markers, and ferroptosis-related indicators were detected. RESULTS: CAL significantly reduced ROS, MDA, and Fe2+ levels, restored MMP and ATP, and upregulated glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11) in OGD-treated cells. These effects were mediated by NRF2/heme oxygenase-1(HO-1) activation, as NRF2 knockdown partially reversed the effect of CAL. In vivo, CAL attenuated myocardial fibrosis, improved cardiac function, and mitigated mitochondrial oxidative damage and ferroptosis the NRF2/HO-1 signaling pathway. CONCLUSIONS: Our findings demonstrated that CAL could ameliorate post-MI HF by attenuating oxidative stress and ferroptosis through the activation of the NRF2/HO-1 signaling pathway.