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

Research output: Contribution to journalArticle

213 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3588-3597
Number of pages10
JournalJournal of Clinical Investigation
Volume118
Issue number11
DOIs
StatePublished - Nov 3 2008

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Energy Metabolism
Fatty Acids
Maintenance
Cardiomegaly
Peroxisome Proliferator-Activated Receptors
Histone Deacetylase Inhibitors
Histone Deacetylases
Oxidative Phosphorylation
Gene Deletion
Cytoplasmic and Nuclear Receptors
Electron Transport
Genes
Protein Isoforms
Triglycerides
Up-Regulation
Alleles
Phenotype
Lipids
Mutation
histone deacetylase 3

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Montgomery, R. L., Potthoff, M. J., Haberland, M., Qi, X., Matsuzaki, S., Humphries, K. M., ... Olson, E. N. (2008). Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. Journal of Clinical Investigation, 118(11), 3588-3597. https://doi.org/10.1172/JCI35847

Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. / Montgomery, Rusty L.; Potthoff, Matthew J.; Haberland, Michael; Qi, Xiaoxia; Matsuzaki, Satoshi; Humphries, Kenneth M.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.

In: Journal of Clinical Investigation, Vol. 118, No. 11, 03.11.2008, p. 3588-3597.

Research output: Contribution to journalArticle

Montgomery, RL, Potthoff, MJ, Haberland, M, Qi, X, Matsuzaki, S, Humphries, KM, Richardson, JA, Bassel-Duby, R & Olson, EN 2008, 'Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice', Journal of Clinical Investigation, vol. 118, no. 11, pp. 3588-3597. https://doi.org/10.1172/JCI35847
Montgomery RL, Potthoff MJ, Haberland M, Qi X, Matsuzaki S, Humphries KM et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. Journal of Clinical Investigation. 2008 Nov 3;118(11):3588-3597. https://doi.org/10.1172/JCI35847
Montgomery, Rusty L. ; Potthoff, Matthew J. ; Haberland, Michael ; Qi, Xiaoxia ; Matsuzaki, Satoshi ; Humphries, Kenneth M. ; Richardson, James A. ; Bassel-Duby, Rhonda ; Olson, Eric N. / Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 11. pp. 3588-3597.
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