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| BRCA1 is a Novel Regulator of Cardiac Function via Altering Myocardial Substrate Utilization and Mitochondrial Bioenergetics |
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Bobby Yanagawa, Praphulla Shukla, Krishna K. Singh, Hwee Teoh, Subodh Verma Division of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada Objective: Improving myocardial metabolism is a novel approach to limit ischemic cardiac dysfunction. We evaluated the effects of BRCA1, a tumor suppressor gene implicated in DNA repair, to regulate myocardial substrate utilization and mitochondrial bioenergetics. Methods: Mice homozygous for exon 11 floxed BRCA1 allele (BRCA1fl/fl) were crossed with heterozygous mice expressing Cre recombinase under the control of the α-myosin heavy chain (αMHC-Cretg/-) promoter. Mice demonstrating the αMHC-Cretg/-;BRCA1fl/fl were identified as cardiomyocyte specific BRCA1 homozygous (CM-BRCA1-/-) and with the αMHC-Cretg/-;BRCA1fl/+ combination as CM-BRCA1+/-. Functional analyses were performed and hearts were submitted for pathological and molecular analyses. Results: Acute and chronic post-MI survival were markedly lower in CM-BRCA1+/- and CM-BRCA1-/- mice compared to WT controls (7d: 92% and 93% vs. 100%; 180d: 43% and 29% vs. 96%; Figure), with early profound ventricular thinning and rupture. Infact sizes were larger in CM-BRCA1+/- (55±7%) and CM-BRCA1-/- (56±9%) mice compared to WT controls (32±23%), with a 1.6-fold increase radius-to-septum thickness consistent with adverse cardiac remodeling. Pressure-volume measurements showed a 2-fold greater end-systolic and end-diastolic volume and a 50% lower ejection fraction in CM-BRCA1-KO mice. Hearts from CM-BRCA1 deficient mice exhibited increased apoptotic Bcl-2 pathway activation and a 3-fold higher expression of γ-H2AX, a marker of double strand DNA damage. Myocardial expression of PPARα and γ, and PPAR-responsive genes, GLUT1, GLUT 4, and the fatty acid transporters CD36 and carnitine palmitoyltransferase 1 were markedly attenuated (p<0.01; Figure). Also reduced transcript expression of acetyl-CoA carboxylase 2 and malonyl-CoA decarboxylase, rate limiting enzymes in fatty acid synthesis, along with a 4-fold reduction in AMP-activated protein kinase expression were shown. From a cellular standpoint these changes likely occurred via a reduction in PPAR-γ coactivator 1α, a key regulator of mitochondrial bioenergetics, which was downregulated in CM-BRCA1-KO hearts (p<0.01). Conclusion: We demonstrate an essential role of BRCA1 as a gatekeeper of cardiac function and survival in response to ischemia. BRCA1 deficiency may result in an energy compromised myocardium, primarily through alterations in myocardial carbohydrate and fatty acid metabolism, likely via a PPAR-dependent mitochondrial bioenergetics.  Figure: A. Reduced overall survival of cardiomyocyte specific BRCA1 homozygous (CM-BRCA1-/-) and heterozygous (CM-BRCA1+/-) knockout mice, compared with WT littermate controls post-MI (**p<0.01). B. Cardiac deletion of BRCA1 alters GLUT 4 transcript expression in hearts post-MI (*p<0.05). Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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