Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice

Rusty L Montgomery; Matthew J Potthoff; Michael Haberland; Xiaoxia Qi; Satoshi Matsuzaki; Kenneth M Humphries; James A Richardson; Rhonda Bassel-Duby; Eric N Olson

doi:10.1172/JCI35847

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Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice

Journal article

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Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice

Rusty L Montgomery, Matthew J Potthoff, Michael Haberland, Xiaoxia Qi, Satoshi Matsuzaki, Kenneth M Humphries, James A Richardson, Rhonda Bassel-Duby and Eric N Olson

The Journal of clinical investigation, Vol.118(11), pp.3588-3597

11/03/2008

DOI: 10.1172/JCI35847

PMCID: PMC2556240

PMID: 18830415

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Abstract

Histone deacetylase (HDAC) inhibitors show remarkable therapeutic potential for a variety of disorders, including cancer, neurological disease, and cardiac hypertrophy. However, the specific HDAC isoforms that mediate their actions are unclear, as are the physiological and pathological functions of individual HDACs in vivo. To explore the role of Hdac3 in the heart, we generated mice with a conditional Hdac3 null allele. Although global deletion of Hdac3 resulted in lethality by E9.5, mice with a cardiac-specific deletion of Hdac3 survived until 3–4 months of age. At this time, they showed massive cardiac hypertrophy and upregulation of genes associated with fatty acid uptake, fatty acid oxidation, and electron transport/oxidative phosphorylation accompanied by fatty acid–induced myocardial lipid accumulation and elevated triglyceride levels. These abnormalities in cardiac metabolism can be attributed to excessive activity of the nuclear receptor PPARα. The phenotype associated with cardiac-specific Hdac3 gene deletion differs from that of all other Hdac gene mutations. These findings reveal a unique role for Hdac3 in maintenance of cardiac function and regulation of myocardial energy metabolism.

Details

Title: Subtitle: Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice
Creators: Rusty L Montgomery - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Matthew J Potthoff - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Michael Haberland - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Xiaoxia Qi - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Satoshi Matsuzaki - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Kenneth M Humphries - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
James A Richardson - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Rhonda Bassel-Duby - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Eric N Olson - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.118(11), pp.3588-3597
DOI: 10.1172/JCI35847
PMID: 18830415
PMCID: PMC2556240
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Language: English
Date published: 11/03/2008
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040210602771

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