Doxorubicin-induced and trastuzumab-induced cardiotoxicity in mice is not prevented by metoprolol
Martin Nicol
Cardiology Department, Lariboisiere Hospital, University of Paris, Paris, France
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorMalha Sadoune
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorEvelyne Polidano
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorJean Marie Launay
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorJane Lise Samuel
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorFeriel Azibani
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorCorresponding Author
Alain Cohen-Solal
Cardiology Department, Lariboisiere Hospital, University of Paris, Paris, France
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Correspondence to: Alain Cohen-Solal, Department of Cardiology, Lariboisiere Hospital, University of Paris, 2 rue Ambroise Paré, 75010 Paris, France.
Email: [email protected]
Search for more papers by this authorMartin Nicol
Cardiology Department, Lariboisiere Hospital, University of Paris, Paris, France
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorMalha Sadoune
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorEvelyne Polidano
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorJean Marie Launay
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorJane Lise Samuel
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorFeriel Azibani
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Search for more papers by this authorCorresponding Author
Alain Cohen-Solal
Cardiology Department, Lariboisiere Hospital, University of Paris, Paris, France
Inserm UMR-S 942, University of Paris, Lariboisiere Hospital, Paris, France
Correspondence to: Alain Cohen-Solal, Department of Cardiology, Lariboisiere Hospital, University of Paris, 2 rue Ambroise Paré, 75010 Paris, France.
Email: [email protected]
Search for more papers by this authorFeriel Azibani and Alain Cohen-Solal contributed equally to this work.
Abstract
Aims
Our objectives were to validate a murine model of chronic cardiotoxicity induced by Doxorubicin (Dox) and Trastuzumab (Trast) and to test the potential cardio-protective effect of metoprolol.
Methods and results
Male C57Bl6 mice were intraperitoneally injected during 2 weeks with Dox (24 mg/kg) or saline, and then with Trast (10 mg/kg) or saline for two more weeks. Half of the mice received metoprolol (100 mg/kg). Cardiotoxicity was defined by a decline in left ventricular ejection fraction (LVEF) ≥ 10 points. At Day 42, Dox + Trast-treated mice exhibited a 13-points decline in LVEF (74 ± 2.6% vs. 87 ± 0.8% for control mice, P < 0.001) and a severe cardiac atrophy (heart weight: 105 ± 2.7 mg vs. 119 ± 3.9 mg for control mice, P < 0.01). This cardiac atrophy resulted from an excess of cardiac necrosis (assessed by plasma cardiac troponin I level: 3.2 ± 0.4 ng/L vs. 1.3 ± 0.06 ng/L for control mice, P < 0.01), an increase in apoptosis (caspase 3 activity showing a six-fold increase for Dox + Trast-treated mice vs. controls, P < 0.001), and cardiomyocyte atrophy (myocyte size: 0.67 ± 0.08 μm2 vs. 1.36 ± 0.10 μm2 for control mice, P < 0.001). In addition, Dox + Trast-treated mice were shown to have an increased cardiac oxidative stress (164 ± 14 dihydroethidine-marked nuclei per area vs. 56 ± 9.5 for control mice, P < 0.01) and increased cardiac fibrosis (the semi-quantitative fibrosis score was three-fold higher for Dox + Trast-treated mice as compared with controls, P < 0.01). Metoprolol was not able to prevent either the decrease in LVEF or the severe cardiac atrophy, the cardiac necrosis, and the cardiac remodelling induced by chemotherapies.
Conclusion
A murine model of chronic cardiotoxicity induced by Dox and Trast was characterized by a decrease in cardiac function, a cardiac apoptosis and necrosis leading to cardiomyocyte atrophy. Metoprolol did not prevent this cardiotoxicity.
Conflict of interest
None declared.
Supporting Information
| Filename | Description |
|---|---|
| ehf213198-sup-0001-Supplementary Figure 1.pdfPDF document, 461.5 KB |
Figure S1. Intracardiac SERCA2a expression at Day 42 (Western Blot) (Ctrl n=4,Ctrl+Meto n=3, Dox+Trast n=5, Dox+Trast+Meto n=4) Values are means ± SEM. *p<0.05 using Anova-2 way test followed by Bonferroni post hoc test. |
| ehf213198-sup-0002-Supplementary Figure 2.pdfPDF document, 438.1 KB |
Figure S2. Intracardiac Caspase 3 acitivity expression at Day 42 (Western Blot) (Ctrl n=4, Ctrl+Meto n=3, Dox+Trast n=5, Dox+Trast+Meto n=4)490 Values are means ± SEM. *p<0.05 using Anova-2 way test followed by Bonferroni post hoc test. |
| ehf213198-sup-0003-Supplementary Figure 3.pdfPDF document, 262.3 KB |
Figure S3. Effect of chemotherapy on cardiac metabolism. A. Intracardiac AMPK expression (Ctrl n=6, Ctrl+Meto n=5, Dox+Trast n=9, Dox+Trast+Meto n=5). B. Intracardiac Sirtuin 3 expression (Ctrl n=6, Ctrl+Meto n=5, Dox+Trast n=9, Dox+Trast+Meto n=5). Values are means ± SEM. *p<0.05 using Anova-2 way test followed by Bonferroni post hoc test. |
| ehf213198-sup-0004-Supplementary Figure 4.pdfPDF document, 508.7 KB |
Figure S4. Murf1 cardiac expression at day 42 (Western Blot). Values are means ±SEM. *p<0.05 using Anova-2 way test followed by Bonferroni post hoc test (Ctrl n=6, Ctrl+Meto n=5, Dox+Trast n=9, Dox+Trast+Meto n=5). |
| ehf213198-sup-0005-Supplementary Table 1.docxWord 2007 document , 15.6 KB |
Table S1. Comparative data between the Dox vs Dox + Trast groups. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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