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Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue
Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplati...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245950/ https://www.ncbi.nlm.nih.gov/pubmed/37292714 http://dx.doi.org/10.1101/2023.05.24.542198 |
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author | Du, Junwei Sudlow, Leland C. Shahverdi, Kiana Zhou, Haiying Michie, Megan Schindler, Thomas H. Mitchell, Joshua D. Mollah, Shamim Berezin, Mikhail Y. |
author_facet | Du, Junwei Sudlow, Leland C. Shahverdi, Kiana Zhou, Haiying Michie, Megan Schindler, Thomas H. Mitchell, Joshua D. Mollah, Shamim Berezin, Mikhail Y. |
author_sort | Du, Junwei |
collection | PubMed |
description | Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with a human equivalent dosage of intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified that oxaliplatin induces strong changes in the heart and affects the heart’s energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such as Nmrk2. Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage. |
format | Online Article Text |
id | pubmed-10245950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-102459502023-06-08 Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue Du, Junwei Sudlow, Leland C. Shahverdi, Kiana Zhou, Haiying Michie, Megan Schindler, Thomas H. Mitchell, Joshua D. Mollah, Shamim Berezin, Mikhail Y. bioRxiv Article Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with a human equivalent dosage of intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified that oxaliplatin induces strong changes in the heart and affects the heart’s energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such as Nmrk2. Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage. Cold Spring Harbor Laboratory 2023-05-25 /pmc/articles/PMC10245950/ /pubmed/37292714 http://dx.doi.org/10.1101/2023.05.24.542198 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Du, Junwei Sudlow, Leland C. Shahverdi, Kiana Zhou, Haiying Michie, Megan Schindler, Thomas H. Mitchell, Joshua D. Mollah, Shamim Berezin, Mikhail Y. Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue |
title | Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue |
title_full | Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue |
title_fullStr | Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue |
title_full_unstemmed | Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue |
title_short | Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue |
title_sort | oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245950/ https://www.ncbi.nlm.nih.gov/pubmed/37292714 http://dx.doi.org/10.1101/2023.05.24.542198 |
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