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Updated: Jun 21, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
A longitudinal evaluation of oxidative stress - mitochondrial dysfunction - ferroptosis genes in
Ren Qianqian1,2, Zhu Peng3, Zhang Licai1,2
1Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Background:
Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study.
Methods:
The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines's interaction with key genes.
Results:
The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines.
Conclusion:
This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.
Insights
Anthracycline-induced cardiotoxicity involves oxidative stress, mitochondrial dysfunction, and ferroptosis (ORMFs). This study identified key ORMFs genes in cardiac microtissues and patient biopsies, revealing their role in immune infiltration and angiogenesis, potentially improving diagnosis and treatment.
Area of Science:
- Cardiology and Molecular Biology
- Investigating the molecular mechanisms of drug-induced heart damage.
Background:
- Antineoplastic medications like doxorubicin can cause cardiotoxicity via oxidative stress, mitochondrial dysfunction, and ferroptosis (ORMFs).
- Understanding the dynamic gene expression related to ORMFs is crucial for addressing anthracycline-induced cardiotoxicity.
Purpose of the Study:
- To analyze the time-resolved measurements of ORMFs genes in response to anthracycline treatment.
- To identify key genes and pathways involved in anthracycline-induced cardiotoxicity using human cardiac models and patient data.
Main Methods:
- Utilized a human 3D cardiac microtissue model and transcriptome data collected over 14 days at therapeutic and toxic doses.
- Employed Weighted Gene Co-expression Network Analysis (WGCNA) to identify key gene modules and functional enrichment analysis (ssGSEA) for biological processes.
- Validated findings using human heart failure patient biopsies and employed molecular docking to assess drug-gene interactions.
Main Results:
- Identified eight key ORMFs genes (CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, VWF), with most down-regulated in anthracycline-treated samples.
- Functional analyses indicated these genes are involved in angiogenesis and immune system pathways.
- ssGSEA revealed significant down-regulation of angiogenesis and immune cell activity in anthracycline-treated settings; RPL8 and CHI3L1 showed binding affinity for anthracyclines.
Conclusions:
- ORMFs genes dynamically respond to anthracycline treatment in cardiac tissues.
- These genes are implicated in immune infiltration and angiogenesis, contributing to anthracycline-induced cardiotoxicity.
- Further understanding of these ORMFs genes may lead to improved diagnostic and therapeutic strategies for cardiotoxicity.
