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Published on: March 29, 2024
Inhibition of ferroptosis reverses heart failure with preserved ejection fraction in mice
Yixiao Xiong1,2, Xin Liu1,2, Ling Jiang3,4
1Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, No 37 Wainan Guoxue Road, Sichuan, 610041, China.
Insights
This study reveals ferroptosis plays a key role in heart failure with preserved ejection fraction (HFpEF). Inhibiting ferroptosis can improve HFpEF symptoms and offers potential therapeutic targets.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure cases.
- The molecular mechanisms underlying HFpEF and impaired diastolic function remain unclear.
- Effective therapeutic targets for HFpEF are limited.
Purpose of the Study:
- To elucidate the molecular mechanisms of HFpEF.
- To identify the role of ferroptosis in HFpEF pathogenesis.
- To discover potential therapeutic targets for HFpEF.
Main Methods:
- Downloaded HFpEF chip data (GSE180065) from NCBI.
- Identified differentially expressed genes (DEGs) and performed GO/KEGG pathway analysis.
- Screened ferroptosis-related hub DEGs using PPI network analysis and validated findings in a HFpEF mouse model.
Main Results:
- DEGs in HFpEF were significantly enriched in ferroptosis-related pathways.
- Identified 11 ferroptosis-related hub DEGs in HFpEF.
- HFpEF mice exhibited abnormal ferroptosis activation, which was ameliorated by ferroptosis inhibitors, altering hub DEG expression.
Conclusions:
- Ferroptosis is implicated in the development of HFpEF.
- Inhibition of ferroptosis may serve as a therapeutic strategy for HFpEF.
- Eleven hub genes represent potential drug targets for HFpEF treatment.
Background:
Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of heart failure cases. The molecular mechanisms by which HFpEF leads to impaired diastolic function of the heart have not been clarified, nor have the drugs that target the clinical symptoms of HFpEF patients.
Methods:
HFpEF chip data (GSE180065) was downloaded from the National Center for Biotechnology Information (NCBI) database. Differentially expressed genes (DEGs) were filtered by the limma package in R and processed for GO and KEGG pathway analyses. Then, ferroptosis-related genes in HFpEF were identified by taking the intersection between DEGs and ferroptosis-related genes. CytoHubba and MCODE were used to screen ferroptosis-related hub DEGs in the protein-protein interaction (PPI) network. Establishment of a mouse HFpEF model to validate the transcript levels of ferroptosis-related hub DEGs and ferroptosis-related phenotypes. Transcript levels of ferroptosis-related hub DEGs and HFpEF phenotypic changes in the hearts of HFpEF mice were further examined after the use of ferroptosis inhibitors.
Results:
GO and KEGG enrichment analyses suggested that the DEGs in HFpEF were significantly enriched in ferroptosis-related pathways. A total of 24 ferroptosis-related DEGs were identified between the ferroptosis gene dataset and the DEGs. The established PPI network was further analyzed by CytoHubba and MCODE modules, and 11 ferroptosis-related hub DEGs in HFpEF were obtained. In animal experiments, HFpEF mice showed significant abnormal activation of ferroptosis. The expression trends of the 11 hub DEGs associated with ferroptosis, except for Cdh1, were consistent with the results of the bioinformatics analysis. Inhibition of ferroptosis alters the transcript levels of 11 ferroptosis-related hub DEGs and ameliorates HFpEF phenotypes.
Conclusions:
The present study contributes to a deeper understanding of the specific mechanisms by which ferroptosis is involved in the development of HFpEF and suggests that inhibition of ferroptosis may mitigate the progression of HFpEF. In addition, eleven hub genes were recognized as potential drug binding targets.
