Abstract 14465: Loss of BRCA2 in the Heart Induces Age-Related Cardiomyopathy
The tumor suppressor gene BRCA2 plays critical roles in DNA repair, cell cycle control and maintenance of genomic stability. 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. To elucidate the role of BRCA2 in the heart and also 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. No basal cardiac phenotype was observed in 12 weeks old CM-BRCA2-/- mice whereas six months old CM-BRCA2-/- mice spontaneously developed marked LV dilatation and systolic failure leading to significantly higher mortality with advanced age (Figure 1). Greater extents of double-strand breaks (DSBs), as evidenced by increased γH2AX foci formation, were observed in LV sections from CM BRCA2-/- mice. We also observed increased activation of BRCA1, CHK1 and ATM in aged CM-BRCA2-/- mice. Foci formation of RAD51, an essential regulator of DSB repair, was absent in the LV sections of CM-BRCA2-/- mice, indicating accumulation of DNA damage over time. Apoptosis, as determined by TUNEL staining and caspase-3 activity, was significantly increased in CM-BRCA2-/- mice, which coincided with increased p53 accumulation, and elevated Bax and PUMA levels. BRCA2 is a novel and previously unrecognized regulator of cardiac structure, function and survival. Cardiac specific BRCA2 loss resulted in a spontaneous age-related phenotype of cardiac failure. BRCA2 may be 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.
- © 2012 by American Heart Association, Inc.