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Updated: Feb 28, 2026
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
Mohamed S Dabour1,2, Ibrahim Y Abdelgawad1, Bushra Sadaf1,3
1Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Abstract:
Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent whose clinical utility is limited by cardiotoxicity. To investigate underlying mechanisms, we employed a multi-omics approach integrating transcriptomics and proteomics, leveraging established mouse models of chronic DOX-induced cardiotoxicity. Methods: 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, temporal comparison was conducted between DEPs in the mice hearts 4 days and 6 weeks post-DOX. Results: 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 h post-DOX. Gene set enrichment analysis (GSEA) revealed upregulated pathways, including p53 signaling, apoptosis, and unfolded protein response. Integrated omics analysis revealed 2089 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. Conclusions: This integrated omics study reveals key molecular pathways and temporal changes in DOX-induced cardiotoxicity, identifying potential biomarkers for future cardioprotective strategies.
Insights
This study reveals key molecular pathways and temporal changes in Doxorubicin (DOX)-induced cardiotoxicity using multi-omics. Findings identify potential biomarkers for developing cardioprotective strategies against chemotherapy side effects.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Oncology
Background:
- Doxorubicin (DOX) is a vital chemotherapy drug, but its use is limited by cardiotoxicity.
- Understanding the molecular mechanisms of DOX-induced cardiotoxicity is crucial for mitigating its adverse effects.
Purpose of the Study:
- To investigate the molecular mechanisms of Doxorubicin (DOX)-induced cardiotoxicity using an integrated transcriptomics and proteomics approach.
- To identify potential biomarkers for early detection and future cardioprotective strategies.
Main Methods:
- Chronic Doxorubicin (DOX) administration in mouse models.
- Bulk RNA sequencing and proteomics analysis of heart tissues.
- Validation of differentially expressed proteins in plasma from Doxorubicin (DOX)-treated breast cancer patients.
Main Results:
- Identified key upregulated genes (e.g., Phlda3, Trp53inp1) and proteins (e.g., Serpina3n, thrombospondin-1).
- Doxorubicin (DOX) exposure led to significant alterations in p53 signaling, apoptosis, and unfolded protein response pathways.
- Plasma SERPINA3 levels were elevated post-Doxorubicin (DOX) treatment in patients, suggesting potential biomarker utility.
Conclusions:
- Integrated multi-omics analysis elucidated critical molecular pathways and temporal dynamics in Doxorubicin (DOX)-induced cardiotoxicity.
- Early responses involve inflammation and apoptosis, while later stages show activation of cell cycle and DNA repair.
- This research identifies novel therapeutic targets and biomarkers for Doxorubicin (DOX) cardioprotection.
