Abstract 13947: Targeting DNA Repair to Prevent Athracycline-induced Cardiac Failure
Anthracycline-based treatment approaches are associated with cardiac dysfunction and remain a significant unmet clinical problem. We hypothesized that strategies aimed at improving DNA repair will promote survival of existing cardiomyocytes, and limit apoptosis in response to doxorubicin. We performed gain- and loss-of-function experiments in isolated neonatal rat cardiomyocytes (NRCM) and in cardiac specific-BRCA1 knockout mice treated with doxorubicin. Indices of apoptosis, double stranded DNA damage, and p53 signaling were evaluated. Adenoviral overexpression of BRCA1 (Ad-BRCA1) protected NRCM against doxorubicin-induced apoptosis, as assessed by flow cytometry and levels of cleaved-caspase-3 (p<0.005). Ad-BRCA1-expressing cells exhibited a profound reduction in p53 in response to doxorubicin (p<0.005). Immunoprecipitation studies showed a distinct physical interaction of BRCA1 with p53. Inhibition of p53 by pifithrin-alpha blocked doxorubicin-induced cardiomyocyte apoptosis in a manner similar to BRCA1. The extent of doxorubicin-induced apoptosis in pifithrin-alpha-treated BRCA1-overexpressing cardiomyocytes was not enhanced suggesting that BRCA1 mainly protects NRCM against apoptosis by reducing p53 levels under genotoxic stress. Ad-BRCA1 delivery completely rescued doxorubicin-treated C57Bl/6 mice from cardiac dysfunction. We generated cardiomyocyte-specific BRCA1-knockout mice and observed that doxorubicin treatment caused a profound reduction in ejection fraction and fractional shortening values in these mice relative to their wild type controls. We report a novel therapeutic approach to limit anthracycline-based cardiac dysfunction in vitro and in vivo by targeting BRCA1, a gene involved in DNA repair. In addition to the immediate implications for cardiovascular repair, these data may have pharmacogenomic implications for the BRCA1 mutation carriers receiving anthracycline-based chemotherapy.
- © 2010 by American Heart Association, Inc.