Abstract 3695: BRCA1 is a Novel Modulator of Cardiac Substrate Metabolism and Restores Cardiac Function in Response to Ischemic and Genotoxic Stressors
BRCA1 is a tumour suppressor gene widely implicated in DNA repair and cellular stress responses. Given the critical role of DNA damage in myocyte survival, we hypothesized that BRCA1 may represent a new molecular target to limit ischemic- and genotoxic stress-induced cardiac remodeling and failure. Murine MI caused a profound 16-fold upregulation in BRCA1 mRNA expression (p<0.01). Cardiomyocyte-specific BRCA1 knockout mice (CM-BRCA1-KO) demonstrated increased susceptibility to MI despite normal cardiac structure and baseline function measurements. CM-BRCA1-KO mice exhibited 32% higher 48 h post-MI mortality, in part, through ventricular free wall rupture (p<0.01) and a 70% higher post-MI mortality at 6 months (p<0.01). This was associated with increased ventricular apoptosis and DNA damage with resultant wall thinning, dilatation and cardiac systolic dysfunction (echo and pressure-volume loops). Similar results were obtained in heterozygous CM-BRCA1-KO and in response to doxorubicin (p<0.001). Ad-BRCA1 overexpression protected neonatal rat cardiomyocytes against doxorubicin and H2O2-induced apoptosis, and in vivo treatment of CM-BRCA-KO mice with Ad-BRCA1 completely rescued doxorubicin-induced cardiac failure (p<0.01). CM-BRCA1-KO mice had reduced myocardial PPARalpha and PPARgamma expression. Expression of PPAR-responsive genes, GLUT1/4 and the fatty acid transporters CD36 and CPT1 were markedly attenuated (p<0.01). CM-BRCA1-KO mice had reduced mRNA expression of ACC2 and MCD, rate limiting enzymes in fatty acid synthesis, along with a 4-fold reduction in AMPK expression. From a cellular standpoint, these changes resulted from a reduction in PGC-1alpha, a key regulator of mitochondrial bioenergetics which was downregulated in CM-BRCA1-KO mouse hearts (p<0.01). We describe a new role of BRCA1 as a cellular gatekeeper of cardiomyocyte apoptosis and susceptibility to ischemic- and genotoxic stress-induced cardiac failure. BRCA1 deficiency may result in an energy compromised myocardium, primarily through alterations in fatty acid synthesis, oxidation and storage, likely via a PPAR-dependent change in mitochondrial bioenergetics. BRCA1-based cell/gene therapy represents a novel treatment for heart failure.