[en] 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.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Haesen, Sibren ; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
Jager, Manon Marie ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) ; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
Brillouet, Aline; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
de Laat, Iris; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
Vastmans, Lotte ; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
Verghote, Eline; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
Delaet, Anouk; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
D'Haese, Sarah ; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium ; Cardiovascular Research Institute Maastricht (CARIM), School for Cardiovascular Diseases, University of Maastricht, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
Hamad, Ibrahim; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium ; VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC) Hasselt University, 3590 Diepenbeek, Belgium
Kleinewietfeld, Markus; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium ; VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research (IRC) Hasselt University, 3590 Diepenbeek, Belgium
Mebis, Jeroen; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium ; Department of Medical Oncology, Jessa Hospital, Stadsomvaart 11, 3500 Hasselt, Belgium
Mullens, Wilfried; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium ; Department of Cardiology, Ziekenhuis Oost Limburg, Schiepse Bos 6, 3600 Genk, Belgium
Lambrichts, Ivo ; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
Wolfs, Esther; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
Deluyker, Dorien; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
Bito, Virginie ; UHasselt, Faculty of Medicine and Life Sciences, Biomedical Research Institute (BIOMED), Agoralaan, 3590 Diepenbeek, Belgium
This research was funded by the Flemish Fund for Scientific Research (FWO Flanders, Brussels, Belgium) with grant numbers 1196221N and G040220FWO, UHasselt Special Research Fund (BOF19KP07) and Limburg Cancer Foundation.
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