Abstract 5356: Brca1 Is An Essential Regulator Of Cardiac Function

Abstract

INTRODUCTION: Preservation of structure and function of the myocardium is critically dependent upon improving the survival of existing cardiomyocytes (CM), through strategies that limit CM apoptosis and DNA damage. BRCA1 is a tumor suppressor gene which functions to promote DNA repair, and protect cells against oxidative and genotoxic stress. We hypothesized that BRCA1 is a novel cellular target to limit CM apoptosis, and prevent aberrant cardiac remodeling. METHODS AND RESULTS: Experimental MI in mice caused a profound 16-fold upregulation in BRCA1 expression, which peaked at 72 hours (p<0.01). In vitro gain-of-function experiments demonstrated that Ad-BRCA1 overexpression protected neonatal rat CM against doxorubicin- and H 2 O 2 -induced apoptosis, as assessed by FACS (p<0.01) and activated caspase-3. Ad-BRCA1-expressing CM exhibited a profound reduction in p53 expression in response to doxorubicin and H 2 O 2 . Co-immunoprecipitation studies demonstrated a distinct physical interaction of BRCA1 with p53. Inhibition of p53, with pifithrin-alpha, blocked doxorubicin-induced CM apoptosis in a manner similar to BRCA1, but BRCA1-overexpressing CM, when treated with doxorubicin did not show further reduction with pifithrin-alpha, indicating an essential requirement of BRCA1 to modulate p53. In vivo gain-of-function studies demonstrated that systemic Ad-BRCA1 delivery completely prevented doxorubicin-induced cardiac dysfunction in mice (echocardiography, p<0.01). In vivo loss-of-function studies were performed in CM -specific BRCA1-KO mice (developed using Cre-lox P technology), which demonstrated marked cardiac dysfunction and mortality in response to doxorubicin administration (p< 0.01 vs. WT + Dox). CONCLUSIONS: We report for the first time an essential role of BRCA1 to limit CM apoptosis, and improve cardiac function in response to genotoxic and oxidative stress. Heart specific deletion of BRCA1 promotes severe systolic dysfunction, and limits survival. In addition to the immediate implications for cardiovascular repair, these data may have ramifications for individuals with BRCA1 mutations or cancer syndromes, particularly in the setting of adjuvant chemotherapy.