Pyridoxamine Limits Cardiac Dysfunction in a Rat Model of Doxorubicin-Induced Cardiotoxicity
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Published:2024-01-17
Issue:1
Volume:13
Page:112
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ISSN:2076-3921
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Container-title:Antioxidants
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language:en
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Short-container-title:Antioxidants
Author:
Haesen Sibren1ORCID, Jager Manon Marie1, Brillouet Aline1, de Laat Iris1, Vastmans Lotte1ORCID, Verghote Eline1, Delaet Anouk1, D’Haese Sarah12ORCID, Hamad Ibrahim13, Kleinewietfeld Markus13, Mebis Jeroen14, Mullens Wilfried15, Lambrichts Ivo1ORCID, Wolfs Esther1, Deluyker Dorien1, Bito Virginie1ORCID
Affiliation:
1. UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium 2. Cardiovascular Research Institute Maastricht (CARIM), School for Cardiovascular Diseases, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands 3. VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC) Hasselt University, 3590 Diepenbeek, Belgium 4. Department of Medical Oncology, Jessa Hospital, Stadsomvaart 11, 3500 Hasselt, Belgium 5. Department of Cardiology, Ziekenhuis Oost Limburg, Schiepse Bos 6, 3600 Genk, Belgium
Abstract
The use of doxorubicin (DOX) chemotherapy is restricted due to dose-dependent cardiotoxicity. Pyridoxamine (PM) is a vitamin B6 derivative with favorable effects on diverse cardiovascular diseases, suggesting a cardioprotective effect on DOX-induced cardiotoxicity. The cardioprotective nature of PM was investigated in a rat model of DOX-induced cardiotoxicity. Six-week-old female Sprague Dawley rats were treated intravenously with 2 mg/kg DOX or saline (CTRL) weekly for eight weeks. Two other groups received PM via the drinking water next to DOX (DOX+PM) or saline (CTRL+PM). Echocardiography, strain analysis, and hemodynamic measurements were performed to evaluate cardiac function. Fibrotic remodeling, myocardial inflammation, oxidative stress, apoptosis, and ferroptosis were evaluated by various in vitro techniques. PM significantly attenuated DOX-induced left ventricular (LV) dilated cardiomyopathy and limited TGF-β1-related LV fibrotic remodeling and macrophage-driven myocardial inflammation. PM protected against DOX-induced ferroptosis, as evidenced by restored DOX-induced disturbance of redox balance, improved cytosolic and mitochondrial iron regulation, and reduced mitochondrial damage at the gene level. In conclusion, PM attenuated the development of cardiac damage after DOX treatment by reducing myocardial fibrosis, inflammation, and mitochondrial damage and by restoring redox and iron regulation at the gene level, suggesting that PM may be a novel cardioprotective strategy for DOX-induced cardiomyopathy.
Funder
Flemish Fund for Scientific Research UHasselt Special Research Fund Limburg Cancer Foundation
Subject
Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology
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