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Updated: Sep 15, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Integrated Omics Approach to Delineate the Mechanisms of Doxorubicin-Induced Cardiotoxicity
Abstract:
Doxorubicin (DOX) is an effective chemotherapy whose clinical utility is limited by cardiotoxicity. To investigate underlying mechanisms, we employed a multi-omics approach integrating transcriptomic and proteomic profiling leveraging established mouse models of chronic DOX- induced cardiotoxicity. Five-week-old male mice received weekly DOX (4 mg/kg) or saline injections for six weeks, with heart tissues harvested 4 days post-treatment. Differentially expressed genes (DEGs) and proteins (DEPs) were identified by bulk RNA-seq and proteomics, validated via qPCR and western blot, respectively Key DEPs were validated in plasma samples from DOX-treated breast cancer patients. Additionally, a temporal comparison was conducted between DEPs in the mice hearts 4 days and 6 weeks post-DOX. RNA-seq revealed upregulation of stress-responsive genes ( Phlda3, Trp53inp1 ) and circadian regulators ( Nr1d1 ), with downregulation of Apelin and Cd74 . Proteomics identified upregulation of serpina3n, thrombospondin-1, and epoxide hydrolase 1. Plasma SERPINA3 concentrations were significantly elevated in breast cancer patients 24 hours post-DOX. Gene set enrichment analysis (GSEA) revealed upregulated pathways including p53 signaling, apoptosis, and unfolded protein response. Integrated omics analysis revealed 2,089 gene-protein pairs. GSEA of concordant gene-protein pairs implicated p53 signaling, apoptosis, and epithelial-mesenchymal transition in upregulated pathways, while oxidative phosphorylation and metabolic pathways were downregulated. Temporal comparison with a delayed timepoint (6 weeks post-DOX) uncovered dynamic remodeling of cardiac signaling, with early response dominated by inflammatory and apoptotic responses, and delayed response marked by cell cycle and DNA repair pathway activation. This integrated-omics study reveals key molecular pathways and temporal changes in DOX-induced cardiotoxicity, identifying potential biomarkers for future cardioprotective strategies.
Insights
Doxorubicin chemotherapy causes heart damage by altering gene and protein expression. This study reveals key molecular pathways and temporal changes, identifying potential biomarkers for new cardioprotective strategies.
Area of Science:
- Cardiology
- Oncology
- Molecular Biology
- Genomics
- Proteomics
Background:
- Doxorubicin (DOX) is a potent chemotherapy drug.
- Its clinical use is limited by cardiotoxicity, a significant side effect.
- Understanding the molecular mechanisms of DOX-induced cardiotoxicity is crucial.
Purpose of the Study:
- To investigate the molecular mechanisms of DOX-induced cardiotoxicity.
- To identify key molecular pathways and temporal changes in cardiac response to DOX.
- To discover potential biomarkers for cardioprotective strategies.
Main Methods:
- Multi-omics approach integrating transcriptomic (RNA-seq) and proteomic profiling in mouse models.
- Differential gene and protein expression analysis.
- Validation using qPCR, western blot, and patient plasma samples.
- Gene Set Enrichment Analysis (GSEA) for pathway analysis.
Main Results:
- Identified differentially expressed genes and proteins in mouse hearts post-DOX treatment.
- Found elevated SERPINA3 in plasma of DOX-treated breast cancer patients.
- GSEA revealed upregulated p53 signaling, apoptosis, and unfolded protein response pathways.
- Integrated omics identified concordant pathways including p53 signaling and apoptosis, with downregulated metabolic pathways.
- Temporal analysis showed distinct early (inflammatory, apoptotic) and delayed (cell cycle, DNA repair) responses.
Conclusions:
- This integrated-omics study elucidates key molecular pathways and temporal dynamics of DOX-induced cardiotoxicity.
- Identified potential biomarkers (e.g., SERPINA3) for early detection and monitoring.
- Findings provide a foundation for developing novel cardioprotective strategies against DOX toxicity.
