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Calycosin protects against post-myocardial infarction heart failure by activating the NRF2/HO-1 signaling pathway
Juan Zhang1, Yilin Zhang2, Zibo Xie2
1The Second Department of Cardiovascular Diseases, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
Insights
Calycosin (CAL) protects against heart failure after myocardial infarction by reducing ferroptosis and oxidative stress. This effect is mediated by activating the NRF2/HO-1 signaling pathway, improving cardiac function.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Myocardial infarction (MI) is a leading cause of heart failure (HF).
- Calycosin (CAL), from Radix astragali, shows potential in improving HF.
- The precise mechanism of CAL's effect on post-MI HF, particularly its link to ferroptosis, requires further investigation.
Purpose of the Study:
- To investigate the cardioprotective effects of Calycosin (CAL) in a post-myocardial infarction heart failure (HF) model.
- To determine if CAL's protective effects are associated with the regulation of ferroptosis.
- To elucidate the role of the NRF2/HO-1 signaling pathway in CAL's mechanism of action.
Main Methods:
- Established in vitro (OGD-induced H9c2 cells) and in vivo (ligation-induced HF rat model) systems.
- Assessed cellular and cardiac markers including reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential (MMP), ATP, Fe2+ levels, and N-terminal pro-brain natriuretic peptide.
- Utilized ferroptosis activator erastin and NRF2 knockdown for rescue experiments, alongside analysis of ferroptosis-related proteins (GPX4, FTH1, SLC7A11) and the NRF2/HO-1 pathway.
Main Results:
- CAL significantly reduced oxidative stress and ferroptosis markers (ROS, MDA, Fe2+) while restoring mitochondrial function (MMP, ATP) in vitro.
- CAL upregulated key ferroptosis suppressors (GPX4, FTH1, SLC7A11) in OGD-treated cells.
- In vivo, CAL improved cardiac function, reduced myocardial fibrosis, and mitigated mitochondrial damage and ferroptosis via NRF2/HO-1 pathway activation.
Conclusions:
- Calycosin (CAL) demonstrates significant cardioprotective effects against post-myocardial infarction heart failure.
- CAL ameliorates cardiac damage by attenuating oxidative stress and ferroptosis.
- The protective mechanism involves the activation of 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.
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