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Regulating cardiac energy metabolism and bioenergetics by targeting the DNA damage repair protein BRCA1.
J Thorac Cardiovasc Surg. 2013 Sep; 146(3):702-9.JT

Abstract

OBJECTIVE

Alterations in cardiac energy and substrate metabolism play a critical role in the development and clinical course of heart failure. We hypothesized that the cardioprotective role of the breast cancer 1, early onset (BRCA1) gene might be mediated in part by alterations in cardiac bioenergetics.

METHODS

We generated cardiomyocyte-specific BRCA1 homozygous and heterozygous knockout mice using the Cre-loxP technology and evaluated the key molecules and pathways involved in glucose metabolism, fatty acid metabolism, and mitochondrial bioenergetics.

RESULTS

Cardiomyocyte-specific BRCA1-deficient mice showed reduced cardiac expression of glucose and fatty acid transporters, reduced acetyl-coenzyme A carboxylase 2 and malonyl-coenzyme A decarboxylase (key enzymes that control malonyl coenzyme A, which in turn controls fatty acid oxidation), and reduced carnitine palmitoyltransferase I, a rate-limiting enzyme for mitochondrial fatty acid uptake. Peroxisome proliferator-activated receptor α and γ and carnitine palmitoyltransferase I levels were also downregulated in these hearts. Rates of glucose and fatty acid oxidation were reduced in the hearts of heterozygous cardiomyocyte-restricted BRCA1-deficient mice, resulting in a decrease in the rate of adenosine triphosphate production. This decrease in metabolism and adenosine triphosphate production occurred despite an increase in 5'-adenosine monophosphate-activated protein kinase and AKT activation in the heart.

CONCLUSIONS

Cardiomyocyte-specific loss of BRCA1 alters critical pathways of fatty acid and glucose metabolism, leading to an energy starved heart. BRCA1-based cell or gene therapy might serve as a novel target to improve cardiac bioenergetics in patients with heart failure.

Authors+Show Affiliations

Division of Cardiac Surgery and Endocrinology, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23317938

Citation

Singh, Krishna K., et al. "Regulating Cardiac Energy Metabolism and Bioenergetics By Targeting the DNA Damage Repair Protein BRCA1." The Journal of Thoracic and Cardiovascular Surgery, vol. 146, no. 3, 2013, pp. 702-9.
Singh KK, Shukla PC, Yanagawa B, et al. Regulating cardiac energy metabolism and bioenergetics by targeting the DNA damage repair protein BRCA1. J Thorac Cardiovasc Surg. 2013;146(3):702-9.
Singh, K. K., Shukla, P. C., Yanagawa, B., Quan, A., Lovren, F., Pan, Y., Wagg, C. S., Teoh, H., Lopaschuk, G. D., & Verma, S. (2013). Regulating cardiac energy metabolism and bioenergetics by targeting the DNA damage repair protein BRCA1. The Journal of Thoracic and Cardiovascular Surgery, 146(3), 702-9. https://doi.org/10.1016/j.jtcvs.2012.12.046
Singh KK, et al. Regulating Cardiac Energy Metabolism and Bioenergetics By Targeting the DNA Damage Repair Protein BRCA1. J Thorac Cardiovasc Surg. 2013;146(3):702-9. PubMed PMID: 23317938.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulating cardiac energy metabolism and bioenergetics by targeting the DNA damage repair protein BRCA1. AU - Singh,Krishna K, AU - Shukla,Praphulla C, AU - Yanagawa,Bobby, AU - Quan,Adrian, AU - Lovren,Fina, AU - Pan,Yi, AU - Wagg,Cory S, AU - Teoh,Hwee, AU - Lopaschuk,Gary D, AU - Verma,Subodh, Y1 - 2013/01/12/ PY - 2012/09/24/received PY - 2012/11/15/revised PY - 2012/12/11/accepted PY - 2013/1/16/entrez PY - 2013/1/16/pubmed PY - 2013/12/16/medline KW - 29 KW - 31.2 KW - 5′-adenosine monophosphate-activated protein kinase KW - ACC KW - AMPK KW - ATP KW - BRCA1 KW - CPT1 KW - CoA KW - GLUT KW - MCD KW - PGC1α KW - PPARs KW - acetyl-coenzyme A carboxylase KW - adenosine triphosphate KW - breast cancer 1, early onset KW - carnitine palmitoyltransferase 1 KW - coenzyme A KW - glucose transporter KW - malonyl-CoA decarboxylase KW - peroxisome proliferator-activated receptor-γ coactivator 1α KW - peroxisome proliferator-activated receptors SP - 702 EP - 9 JF - The Journal of thoracic and cardiovascular surgery JO - J Thorac Cardiovasc Surg VL - 146 IS - 3 N2 - OBJECTIVE: Alterations in cardiac energy and substrate metabolism play a critical role in the development and clinical course of heart failure. We hypothesized that the cardioprotective role of the breast cancer 1, early onset (BRCA1) gene might be mediated in part by alterations in cardiac bioenergetics. METHODS: We generated cardiomyocyte-specific BRCA1 homozygous and heterozygous knockout mice using the Cre-loxP technology and evaluated the key molecules and pathways involved in glucose metabolism, fatty acid metabolism, and mitochondrial bioenergetics. RESULTS: Cardiomyocyte-specific BRCA1-deficient mice showed reduced cardiac expression of glucose and fatty acid transporters, reduced acetyl-coenzyme A carboxylase 2 and malonyl-coenzyme A decarboxylase (key enzymes that control malonyl coenzyme A, which in turn controls fatty acid oxidation), and reduced carnitine palmitoyltransferase I, a rate-limiting enzyme for mitochondrial fatty acid uptake. Peroxisome proliferator-activated receptor α and γ and carnitine palmitoyltransferase I levels were also downregulated in these hearts. Rates of glucose and fatty acid oxidation were reduced in the hearts of heterozygous cardiomyocyte-restricted BRCA1-deficient mice, resulting in a decrease in the rate of adenosine triphosphate production. This decrease in metabolism and adenosine triphosphate production occurred despite an increase in 5'-adenosine monophosphate-activated protein kinase and AKT activation in the heart. CONCLUSIONS: Cardiomyocyte-specific loss of BRCA1 alters critical pathways of fatty acid and glucose metabolism, leading to an energy starved heart. BRCA1-based cell or gene therapy might serve as a novel target to improve cardiac bioenergetics in patients with heart failure. SN - 1097-685X UR - https://www.unboundmedicine.com/medline/citation/23317938/Regulating_cardiac_energy_metabolism_and_bioenergetics_by_targeting_the_DNA_damage_repair_protein_BRCA1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-5223(12)01594-2 DB - PRIME DP - Unbound Medicine ER -