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

Yixiao Xiong; Xin Liu; Ling Jiang; Tao Hao; Yanyan Wang; Tao Li

doi:10.1186/s12967-023-04734-y

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

J Transl Med. 2024 Feb 24;22(1):199. doi: 10.1186/s12967-023-04734-y.

Authors

Yixiao Xiong^#^{1

2}, Xin Liu^#^{1

2}, Ling Jiang^#^{3

4}, Tao Hao⁵, Yanyan Wang⁶, Tao Li^{7

8}

Affiliations

¹ Department 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.
² Laboratory of Mitochondria and Metabolism, West China Hospital, Sichuan University, Sichuan, 610041, China.
³ Department of Anesthesiology, West China Second Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
⁴ Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu, 610041, Sichuan, China.
⁵ Department of Gastroenterology, Chengdu Fifth People's Hospital, No. 33 Mashi Street, Chengdu, 611130, Sichuan, China.
⁶ Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, No 37 Wainan Guoxue Road, Chengdu, 610041, Sichuan, China. kittyanwang520@scu.edu.cn.
⁷ Department 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. scutaoli1981@scu.edu.cn.
⁸ Laboratory of Mitochondria and Metabolism, West China Hospital, Sichuan University, Sichuan, 610041, China. scutaoli1981@scu.edu.cn.

^# Contributed equally.

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.

Keywords: Bioinformatics analysis; Deferiprone; Ferroptosis; Ferrostatin-1; Heart failure with preserved ejection fraction.

MeSH terms

Animals
Computational Biology
Disease Models, Animal
Ferroptosis*
Heart
Heart Failure* / drug therapy
Heart Failure* / genetics
Humans
Mice
Stroke Volume

Abstract

MeSH terms

Grants and funding