Abstract 11516: BRCA1 Induces Cardiac Protection Through a P53-Dependent Pathway
Recent data implicate BRCA1, the DNA-damage repair protein, as an essential regulator of cardiac structure and function. We hypothesized that BRCA1 regulates p53-mediated cardiomyocyte apoptosis and attenuates cardiac failure. Cardiomyocyte specific BRCA1 knockout mice (CM-BRCA1-/-) exhibited cardiac dysfunction with increased mortality in response to experimental myocardial infarction (MI) or genotoxic stress with doxorubicin. Increased total p53 expression was observed in the hearts of CM-BRCA1-/- mice relative to that in hearts from control littermates post-MI. The increase in cardiomyocyte apoptosis noted in CM-BRCA1+/- and CM-BRCA1-/- mice was associated with a loss of myocardial pro-survival Bcl-2 with concomitant increase in pro-apoptotic Bax leading to a ~12.5 fold increase in the Bax:Bcl-2 ratio, hence shifting the balance from a survival to apoptotic milieu. This was associated with elevated levels of total and cleaved caspase-3 compared to the corresponding control group. A ~2.5-fold higher expression of γH2A.X, an indicator of double strand DNA breaks, was observed in hearts from CM-BRCA1-/- mice compared to control animals 48 h after experimental MI-induction. After three days, this DNA damage signal was resolved in control mice but a persistent γH2A.X signal was observed in the left ventricular sections of CM-BRCA1-/- mice. Although control mice exhibited evidence of post-MI RAD51-foci formation, such foci were largely absent in CM-BRCA1-/- mice. We crossed αMHC-Cretg/;BRCA1fl/fl mice with p53+/- mutants to generate mice with deletion of one allele of BRCA1 in their cardiomyocytes along with the systemic loss of one allele of p53 (αMHC-Cretg/;BRCA1fl/+;p53+/- otherwise denoted as CM-BRCA1+/-;p53+/-). CM-BRCA1+/-;p53+/- mice were protected against ischemia-induced apoptosis and cardiac failure compared to CM-BRCA1+/- mice. We generated compound heterozygous BRCA1+/Δ11;p53+/- mice and found that systemic loss of one allele of p53 rescued BRCA1+/Δ11 heterozygous mice against ischemia-induced cardiac dysfunction. In conclusion, loss of BRCA1 provokes ischemia-induced cardiomyocyte apoptosis through alterations in the p53-mediated cell death pathway, which is causally implicated in ischemic heart failure.
- © 2011 by American Heart Association, Inc.