The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases
The cardiotoxicity of doxorubicin (DOX) may manifest at the beginning/during treatment or years after, compromising patients’ quality of life. We intended to study the cardiac pathways one week (short-term, control 1 [CTRL1] and DOX1 groups) or five months (long-term, CTRL2 and DOX2 groups) after DO...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/11/1613 |
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| author | Sofia Reis Brandão Ana Reis-Mendes Maria João Neuparth Félix Carvalho Rita Ferreira Vera Marisa Costa |
| author_facet | Sofia Reis Brandão Ana Reis-Mendes Maria João Neuparth Félix Carvalho Rita Ferreira Vera Marisa Costa |
| author_sort | Sofia Reis Brandão |
| collection | DOAJ |
| description | The cardiotoxicity of doxorubicin (DOX) may manifest at the beginning/during treatment or years after, compromising patients’ quality of life. We intended to study the cardiac pathways one week (short-term, control 1 [CTRL1] and DOX1 groups) or five months (long-term, CTRL2 and DOX2 groups) after DOX administration in adult male CD-1 mice. Control groups were given saline, and DOX groups received a 9.0 mg/Kg cumulative dose. In the short-term, DOX decreased the content of AMP-activated protein kinase (AMPK) while the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) increased compared to CTRL1, suggesting the upregulation of fatty acids oxidation. Moreover, mitofusin1 (Mfn1) content was decreased in DOX1, highlighting decreased mitochondrial fusion. In addition, increased B-cell lymphoma-2 associated X-protein (BAX) content in DOX1 pointed to the upregulation of apoptosis. Conversely, in the long-term, DOX decreased the citrate synthase (CS) activity and the content of Beclin1 and autophagy protein 5 (ATG5) compared to CTRL2, suggesting decreased mitochondrial density and autophagy. Our study demonstrates that molecular mechanisms elicited by DOX are modulated at different extents over time, supporting the differences on clinic cardiotoxic manifestations with time. Moreover, even five months after DOX administration, meaningful heart molecular changes occurred, reinforcing the need for the continuous cardiac monitoring of patients and determination of earlier biomarkers before clinical cardiotoxicity is set. |
| first_indexed | 2024-03-09T16:32:51Z |
| format | Article |
| id | doaj.art-ed102a755f064b06b16eed083f7c98fd |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T16:32:51Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-ed102a755f064b06b16eed083f7c98fd2023-11-24T15:00:34ZengMDPI AGPharmaceuticals1424-82472023-11-011611161310.3390/ph16111613The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy IncreasesSofia Reis Brandão0Ana Reis-Mendes1Maria João Neuparth2Félix Carvalho3Rita Ferreira4Vera Marisa Costa5Associate Laboratory i4HB—Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, PortugalAssociate Laboratory i4HB—Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, PortugalLaboratory for Integrative and Translational Research in Population Health (ITR), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sports, University of Porto, 4200-450 Porto, PortugalAssociate Laboratory i4HB—Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, PortugalLAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, PortugalAssociate Laboratory i4HB—Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, PortugalThe cardiotoxicity of doxorubicin (DOX) may manifest at the beginning/during treatment or years after, compromising patients’ quality of life. We intended to study the cardiac pathways one week (short-term, control 1 [CTRL1] and DOX1 groups) or five months (long-term, CTRL2 and DOX2 groups) after DOX administration in adult male CD-1 mice. Control groups were given saline, and DOX groups received a 9.0 mg/Kg cumulative dose. In the short-term, DOX decreased the content of AMP-activated protein kinase (AMPK) while the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) increased compared to CTRL1, suggesting the upregulation of fatty acids oxidation. Moreover, mitofusin1 (Mfn1) content was decreased in DOX1, highlighting decreased mitochondrial fusion. In addition, increased B-cell lymphoma-2 associated X-protein (BAX) content in DOX1 pointed to the upregulation of apoptosis. Conversely, in the long-term, DOX decreased the citrate synthase (CS) activity and the content of Beclin1 and autophagy protein 5 (ATG5) compared to CTRL2, suggesting decreased mitochondrial density and autophagy. Our study demonstrates that molecular mechanisms elicited by DOX are modulated at different extents over time, supporting the differences on clinic cardiotoxic manifestations with time. Moreover, even five months after DOX administration, meaningful heart molecular changes occurred, reinforcing the need for the continuous cardiac monitoring of patients and determination of earlier biomarkers before clinical cardiotoxicity is set.https://www.mdpi.com/1424-8247/16/11/1613cardio-oncologydoxorubicinenergetic metabolismapoptosisautophagy |
| spellingShingle | Sofia Reis Brandão Ana Reis-Mendes Maria João Neuparth Félix Carvalho Rita Ferreira Vera Marisa Costa The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases Pharmaceuticals cardio-oncology doxorubicin energetic metabolism apoptosis autophagy |
| title | The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases |
| title_full | The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases |
| title_fullStr | The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases |
| title_full_unstemmed | The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases |
| title_short | The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases |
| title_sort | metabolic fingerprint of doxorubicin induced cardiotoxicity in male cd 1 mice fades away with time while autophagy increases |
| topic | cardio-oncology doxorubicin energetic metabolism apoptosis autophagy |
| url | https://www.mdpi.com/1424-8247/16/11/1613 |
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