Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice.
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 PPARalpha. 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.
Montgomery
Rusty L
RL
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Potthoff
Matthew J
MJ
Haberland
Michael
M
Qi
Xiaoxia
X
Matsuzaki
Satoshi
S
Humphries
Kenneth M
KM
Richardson
James A
JA
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D006321:Heart; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D047493:PPAR alpha / Q000378:metabolism; D015854:Up-Regulation; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D047493:PPAR alpha; D000099186:Histone Deacetylase 3