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Translational Proteomics Analysis of Anthracycline-Induced Cardiotoxicity From Cardiac Microtissues to Human Heart
Nhan Nguyen1, Terezinha Souza1, Marcha C T Verheijen1
1Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.
Abstract:
Anthracyclines, including doxorubicin, idarubicin, and epirubicin, are common antitumor drugs as well as well-known cardiotoxic agents. This study analyzed the proteomics alteration in cardiac tissues caused by these 3 anthracyclines analogs. The in vitro human cardiac microtissues were exposed to drugs in 2 weeks; the proteomic data were measured at 7 time points. The heart biopsy data were collected from heart failure patients, in which some patients underwent anthracycline treatment. The anthracyclines-affected proteins were separately identified in the in vitro and in vivo dataset using the WGCNA method. These proteins engage in different cellular pathways including translation, metabolism, mitochondrial function, muscle contraction, and signaling pathways. From proteins detected in 2 datasets, a protein-protein network was established with 4 hub proteins, and 7 weighted proteins from both cardiac microtissue and human biopsies data. These 11 proteins, which involve in mitochondrial functions and the NF-κB signaling pathway, could provide insights into the anthracycline toxic mechanism. Some of them, such as HSPA5, BAG3, and SH3BGRL, are cardiac therapy targets or cardiotoxicity biomarkers. Other proteins, such as ATP5F1B and EEF1D, showed similar responses in both the in vitro and in vivo data. This suggests that the in vitro outcomes could link to clinical phenomena in proteomic analysis.
Insights
This study investigated anthracycline cardiotoxicity by analyzing protein changes in cardiac cells and patient biopsies. Key proteins involved in mitochondrial function and NF-κB signaling were identified, offering insights into drug toxicity mechanisms.
Area of Science:
- Proteomics
- Cardiotoxicity
- Drug Discovery
Background:
- Anthracyclines (doxorubicin, idarubicin, epirubicin) are vital antitumor drugs but cause significant cardiotoxicity.
- Understanding the molecular mechanisms of anthracycline-induced heart damage is crucial for patient safety and developing targeted therapies.
Purpose of the Study:
- To analyze proteomic alterations in cardiac tissues induced by anthracycline analogs.
- To identify key proteins and pathways involved in anthracycline cardiotoxicity using both in vitro and in vivo models.
- To establish a protein-protein interaction network for potential therapeutic targets and biomarkers.
Main Methods:
- Proteomic analysis of human cardiac microtissues exposed to anthracyclines over 7 time points.
- Analysis of heart biopsy data from heart failure patients, including those treated with anthracyclines.
- Weighted Gene Co-expression Network Analysis (WGCNA) to identify affected proteins in both datasets.
- Construction of a protein-protein interaction network to pinpoint hub and weighted proteins.
Main Results:
- Proteins involved in translation, metabolism, mitochondrial function, muscle contraction, and signaling pathways were identified.
- A network of 11 proteins (4 hub, 7 weighted) was established from combined in vitro and in vivo data.
- These proteins are implicated in mitochondrial functions and the NF-κB signaling pathway, shedding light on cardiotoxicity mechanisms.
- Proteins like HSPA5, BAG3, and SH3BGRL show potential as cardiac therapy targets or cardiotoxicity biomarkers.
- Similar protein responses were observed between in vitro and in vivo data (e.g., ATP5F1B, EEF1D), validating the in vitro model.
Conclusions:
- The study identified key proteins and pathways contributing to anthracycline cardiotoxicity.
- The findings suggest that in vitro proteomic data can predict clinical cardiotoxicity phenomena.
- Identified proteins offer potential targets for novel cardiotoxicity biomarkers and therapeutic strategies.
