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Hepatocyte growth factor alleviates alcoholic cardiomyopathy through the Nrf2 pathway-a focus on iron metabolism
Yichao Yu1, Ji Chen2, Kejiang Cao3
1Department of Cardiology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China.
Insights
Hepatocyte growth factor (HGF) protects against alcoholic cardiomyopathy by inhibiting ferroptosis. HGF reduces iron accumulation in heart cells via the Nrf2 pathway, offering a potential therapeutic strategy.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Toxicology
Background:
- Alcohol misuse is a significant cause of cardiomyopathy.
- Hepatocyte growth factor (HGF) and iron metabolism are implicated in cardiovascular diseases.
- This study investigates HGF's role in regulating cardiac ferroptosis.
Purpose of the Study:
- To determine if HGF regulates cardiac ferroptosis.
- To elucidate the mechanism by which HGF affects ferroptosis in alcoholic cardiomyopathy.
- To identify potential therapeutic targets for alcoholic cardiomyopathy.
Main Methods:
- Established alcoholic cardiomyopathy models in male Sprague Dawley rats.
- Assessed HGF's effect on cardiomyocyte ferroptosis using fluorescence quantification, ELISA, CCK8, and calcein staining.
- Investigated the role of Nuclear factor erythroid 2-related factor 2 (Nrf2) in mediating HGF's protective effects against ferroptosis and regulating iron metabolism proteins.
Main Results:
- HGF suppressed cardiac ferroptosis via the Nrf2 pathway.
- HGF modulated iron metabolism by decreasing ferritin heavy chain 1 (FTH1) and increasing ferroportin (Fpn1) and divalent metal-ion transporter 1 (DMT1).
- Nrf2 knockdown reversed HGF's protective effects, including reduced lipid peroxidation, labile iron pool (LIP), and normalized iron-related protein levels.
Conclusions:
- HGF is a protective factor against alcoholic cardiomyopathy by inhibiting cardiac ferroptosis.
- HGF acts through the Nrf2 pathway to reduce iron storage and increase iron export in cardiomyocytes.
- This mechanism lowers the iron load in heart cells, offering a novel therapeutic approach for alcoholic cardiomyopathy.
Background:
Alcohol misuse leads to cardiomyopathy. Hepatocyte growth factor (HGF) concentrations and iron metabolism fluctuations are both associated with cardiovascular diseases. This investigation is designed to test if and how HGF regulates cardiac ferroptosis.
Methods:
Male Sprague Dawley rats were used to establish animal models. Exogenous HGF's potential to reduce cardiomyocyte ferroptosis, which is typified by varying labile iron pool (LIP), elevated lipid peroxidation, and diminished cell survival, was examined by fluorescence quantification, enzyme-linked immunosorbent assay (ELISA), Cell Counting Kit-8 (CCK8) and calcein staining. Nuclear factor erythroid 2-related factor 2 (Nfe2l2/Nrf2) was then screened by a public database as a potential target for HGF to block myocardial ferroptosis. Subsequently, Nfe2l2 knockdown was induced to verify Nrf2's mediating role for HGF's protection against myocardial ferroptosis, as well as HGF's particular effects on proteins involved in iron absorption, storage, and excretion.
Results:
HGF suppressed cardiac ferroptosis through Nfe2l2/Nrf2-related pathway, showing a decline in ferritin heavy chain 1 (FTH1) and an elevation in ferroportin (Fpn1) and divalent metal-ion transporter 1 (DMT1). Knockdown of Nfe2l2 reversed the protective effect against the promotion of lipid peroxidation and LIP in ethanol-induced cardiomyocytes, as well as changes in iron-related proteins.
Conclusions:
HGF functions as a potent protective factor for alcoholic cardiomyopathy (ACM) by inhibiting cardiac ferroptosis via Nfe2l2/Nrf2-related pathway, and the effect is achieved by reducing iron storage while increasing iron exportation, thus lowering iron load in cardiomyocytes.
