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Updated: Jun 11, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Dexrazoxane prevents vascular toxicity in doxorubicin-treated mice
Dustin N Krüger1, Matthias Bosman2, Emeline M Van Craenenbroeck3,4
1Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, Antwerp, B-2610, Belgium. dustin.kruger@uantwerpen.be.
Background:
Doxorubicin (DOX) is used for breast cancer and lymphoma, but can cause cardiotoxicity, arterial stiffness, and endothelial dysfunction. We recently reported SERPINA3N as biomarker of cardiovascular toxicity in patients and mice. Dexrazoxane (DEXRA) is an FDA-approved drug that prevents DOX-induced cardiac toxicity in high-risk patients. However, the effect of DEXRA on vascular dysfunction during DOX treatment has not been documented. Therefore, here we investigated whether DEXRA protects against DOX-induced arterial stiffness, endothelial dysfunction, and SERPINA3N upregulation in tissue and plasma from mice.
Methods:
Male C57BL6/J mice were treated with DOX (4 mg/kg), DEXRA (40 mg/kg), a combination (DEXRA + DOX), or VEHICLE (0.9% NaCl) weekly i.p. for 6 weeks (n = 8 per group). Cardiovascular function was measured in vivo by ultrasound imaging at baseline, weeks 2 and 6. Vascular reactivity was analyzed ex vivo in the thoracic aorta at week 6 and molecular analysis was performed.
Results:
DEXRA prevented left ventricular ejection fraction decline by DOX (DEXRA + DOX: 62 ± 2% vs DOX: 51 ± 2%). Moreover, DEXRA prevented the increase in pulse wave velocity by DOX (DEXRA + DOX: 2.1 ± 0.2 m/s vs DOX: 4.5 ± 0.3 m/s) and preserved endothelium-dependent relaxation (DEXRA + DOX: 82 ± 3% vs DOX: 62 ± 3%). In contrast to DOX-treated mice, SERPINA3N did not increase in the DEXRA + DOX group.
Conclusion:
Our results not only confirm the cardioprotective effects of DEXRA against DOX-induced cardiotoxicity but also add preservation of vascular endothelial cell function as an important mechanism. Moreover, the study demonstrates the potential of SERPINA3N as a biomarker for monitoring cardiovascular complications of DOX in high-risk patients.
Insights
Dexrazoxane (DEXRA) prevents doxorubicin (DOX)-induced heart damage and vascular dysfunction. DEXRA also inhibited SERPINA3N upregulation, suggesting its potential as a biomarker for DOX cardiovascular toxicity.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Oncology
Background:
- Doxorubicin (DOX) is a chemotherapy agent used for breast cancer and lymphoma.
- DOX treatment can lead to cardiotoxicity, arterial stiffness, and endothelial dysfunction.
- SERPINA3N has been identified as a biomarker for cardiovascular toxicity associated with DOX.
- Dexrazoxane (DEXRA) is an FDA-approved drug that protects against DOX-induced cardiac toxicity.
Purpose of the Study:
- To investigate the protective effects of DEXRA against DOX-induced arterial stiffness and endothelial dysfunction.
- To determine if DEXRA prevents SERPINA3N upregulation in mice treated with DOX.
Main Methods:
- Male C57BL6/J mice received weekly intraperitoneal injections of DOX, DEXRA, DEXRA + DOX, or vehicle for six weeks.
- Cardiovascular function was assessed using ultrasound imaging at baseline, week 2, and week 6.
- Vascular reactivity was analyzed ex vivo in the thoracic aorta, and molecular analysis was performed.
Main Results:
- DEXRA treatment preserved left ventricular ejection fraction in mice receiving DOX.
- DEXRA prevented the increase in pulse wave velocity and preserved endothelium-dependent relaxation in DOX-treated mice.
- SERPINA3N levels did not increase in mice treated with DEXRA + DOX, unlike in the DOX-only group.
Conclusions:
- DEXRA demonstrates cardioprotective effects against DOX-induced cardiotoxicity.
- DEXRA preserves vascular endothelial cell function, adding to its protective mechanisms.
- SERPINA3N shows potential as a biomarker for monitoring DOX-related cardiovascular complications in high-risk patients.
