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Updated: May 26, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
BRCA2 protein deficiency exaggerates doxorubicin-induced cardiomyocyte apoptosis and cardiac failure
Krishna K Singh1, Praphulla C Shukla, Adrian Quan
1Division of Cardiac Surgery, The Keenan Research Centre in the Li Ka Shing Knowledge Institute of St.Michael’s Hospital,Toronto, Ontario M5B 1W8, Canada.
Abstract:
The tumor suppressor breast cancer susceptibility gene 2 (BRCA2) plays an important role in the repair of DNA damage, and loss of BRCA2 predisposes carriers to breast and ovarian cancers. Doxorubicin (DOX) remains the cornerstone of chemotherapy in such individuals. However, it is often associated with cardiac failure, which once manifests carries a poor prognosis. Because BRCA2 regulates genome-wide stability and facilitates DNA damage repair, we hypothesized that loss of BRCA2 may increase susceptibility to DOX-induced cardiac failure. To this aim, we generated cardiomyocyte-specific BRCA2 knock-out (CM-BRCA2(-/-)) mice using the Cre-loxP technology and evaluated their basal and post-DOX treatment phenotypes. Although CM-BRCA2(-/-) mice exhibited no basal cardiac phenotype, DOX treatment resulted in markedly greater cardiac dysfunction and mortality in CM-BRCA2(-/-) mice compared with control mice. Apoptosis in left ventricular (LV) sections from CM-BRCA2(-/-) mice compared with that in corresponding sections from wild-type (WT) littermate controls was also significantly enhanced after DOX treatment. Microscopic examination of LV sections from DOX-treated CM-BRCA2(-/-) mice revealed a greater number of DNA double-stranded breaks and the absence of RAD51 focus formation, an essential marker of double-stranded break repair. The levels of p53 and the p53-related proapoptotic proteins p53-up-regulated modulator of apoptosis (PUMA) and Bax were significantly increased in samples from CM-BRCA2(-/-) mice. This corresponded with increased Bax to Bcl-2 ratios and elevated cytochrome c release in the LV sections of DOX-treated CM-BRCA2(-/-) mice. Taken together, these data suggest a critical and previously unrecognized role of BRCA2 as a gatekeeper of DOX-induced cardiomyocyte apoptosis and susceptibility to overt cardiac failure. Pharmacogenomic studies evaluating cardiac function in BRCA2 mutation carriers treated with doxorubicin are encouraged.
Insights
Loss of breast cancer susceptibility gene 2 (BRCA2) in heart cells increases susceptibility to doxorubicin-induced cardiac failure. BRCA2 deficiency impairs DNA repair, leading to cardiomyocyte apoptosis and mortality after doxorubicin treatment.
Area of Science:
- Cardiology
- Oncology
- Genetics
Background:
- Breast cancer susceptibility gene 2 (BRCA2) is crucial for DNA repair.
- Doxorubicin (DOX) chemotherapy is vital for BRCA2 mutation carriers but causes cardiac failure.
- BRCA2's role in preventing DOX-induced cardiotoxicity is unknown.
Purpose of the Study:
- To investigate the role of BRCA2 in cardiomyocyte DNA repair and doxorubicin-induced cardiotoxicity.
- To determine if loss of BRCA2 in cardiomyocytes exacerbates doxorubicin-induced cardiac dysfunction and mortality.
Main Methods:
- Generated cardiomyocyte-specific BRCA2 knock-out (CM-BRCA2(-/-)) mice.
- Administered doxorubicin (DOX) to CM-BRCA2(-/-) and wild-type (WT) littermate controls.
- Assessed cardiac function, mortality, apoptosis, DNA damage, and protein markers.
Main Results:
- CM-BRCA2(-/-) mice showed significantly increased DOX-induced cardiac dysfunction and mortality compared to WT controls.
- DOX treatment led to enhanced cardiomyocyte apoptosis, DNA double-stranded breaks, and impaired RAD51 focus formation in CM-BRCA2(-/-) mice.
- Increased p53, PUMA, Bax, and cytochrome c release were observed in DOX-treated CM-BRCA2(-/-) hearts.
Conclusions:
- BRCA2 acts as a critical gatekeeper protecting cardiomyocytes from DOX-induced apoptosis and cardiac failure.
- Loss of BRCA2 function in cardiomyocytes significantly increases susceptibility to doxorubicin cardiotoxicity.
- Pharmacogenomic studies on BRCA2 mutation carriers receiving doxorubicin are warranted.
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