Abstract 11502: Cardiac-Specific Disruption of BRCA2 Results in Higher Doxorubicin Sensitivity and Heart Failure with Advanced Age
Unresolved DNA damage is a critical component of progressive cardiomyocyte apoptosis and has been implicated in the transition towards overt cardiac failure. Since BRCA2 regulates genome wide stability and affords DNA damage repair, we hypothesized that it may be an essential regulator of cardiac function under basal and stress-induced conditions. To elucidate the role of BRCA2 in cardiac structure and function and to circumvent the embryonic lethality associated with systemic BRCA2 loss, we generated cardiomyocyte-specific BRCA2-knockout (CM-BRCA2-/-) mice using the Cre-loxP technology. CM-BRCA2-/- mice were viable and born in expected Mendelian ratios. Genotoxic stress via doxorubicin (DOX) treatment markedly reduced ejection fraction and fractional shortening in CM-BRCA2-/- mice vs. WT littermate controls, with maladaptive left ventricular (LV) dilatation and remodeling, and significantly higher mortality. Greater extent of double-strand breaks (DSBs) as evidenced by γH2AX foci formation, elevated ATM and phosphorylated BRCA1 levels, and increased ratios of TUNEL-positive nuclei were found in LV sections from CM-BRCA2-/- mice vs. WT mice (all p<0.01). Apoptosis, as determined by caspase-3 activity, was significantly increased in DOX-treated CM-BRCA2-/- mice, coincident with increased p53 accumulation, raised cytochrome c release and elevated Bax and PUMA levels. Foci formation of RAD51, an essential regulator of DSB repair, was absent in LV sections of DOX-treated CM-BRCA2-/- mice. No basal cardiac phenotype was observed in 12 weeks old CM-BRCA2-/- mice but six months old CM-BRCA2-/- mice spontaneously developed marked LV dilatation and systolic failure, coincident with increased DSB breaks and upregulated p53-mediated apoptotic responses. BRCA2 is a novel and previously unrecognized regulator of cardiac structure, function and survival. Cardiac specific BRCA2 loss results in a spontaneous age-related phenotype of cardiac failure and higher sensitivity to genotoxic-stress induced maladaptive remodeling and death. BRCA2 is a novel candidate gene for heart failure therapeutics and individuals with BRCA2 mutations may be at a heightened and previously unrecognized risk of cardiac failure, in addition to cancer syndromes.
- © 2011 by American Heart Association, Inc.