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Journal of Translational Medicine

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Open Access 01-12-2024 | Heart Failure | Research

Inhibition of ferroptosis reverses heart failure with preserved ejection fraction in mice

Authors: Yixiao Xiong, Xin Liu, Ling Jiang, Tao Hao, Yanyan Wang, Tao Li

Published in: Journal of Translational Medicine | Issue 1/2024

Abstract

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.

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Title: Inhibition of ferroptosis reverses heart failure with preserved ejection fraction in mice
Authors: Yixiao Xiong
Xin Liu
Ling Jiang
Tao Hao
Yanyan Wang
Tao Li
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Heart Failure
Published in: Journal of Translational Medicine / Issue 1/2024
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-023-04734-y

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