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PMID:17322895

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Citation

Trivedi, CM, Luo, Y, Yin, Z, Zhang, M, Zhu, W, Wang, T, Floss, T, Goettlicher, M, Noppinger, PR, Wurst, W, Ferrari, VA, Abrams, CS, Gruber, PJ and Epstein, JA (2007) Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat. Med. 13:324-31

Abstract

In the adult heart, a variety of stresses induce re-expression of a fetal gene program in association with myocyte hypertrophy and heart failure. Here we show that histone deacetylase-2 (Hdac2) regulates expression of many fetal cardiac isoforms. Hdac2 deficiency or chemical histone deacetylase (HDAC) inhibition prevented the re-expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp5f) resulting in constitutive activation of glycogen synthase kinase 3beta (Gsk3beta) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1). In contrast, Hdac2 transgenic mice had augmented hypertrophy associated with inactivated Gsk3beta. Chemical inhibition of activated Gsk3beta allowed Hdac2-deficient adults to become sensitive to hypertrophic stimulation. These results suggest that Hdac2 is an important molecular target of HDAC inhibitors in the heart and that Hdac2 and Gsk3beta are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Links

PubMed Online version:10.1038/nm1552

Keywords

Animals; Cardiomegaly/embryology; Cardiomegaly/enzymology; Cardiomegaly/genetics; Enzyme Activation/physiology; Fetus; Glycogen Synthase Kinase 3/metabolism; Histone Deacetylase 2; Histone Deacetylases/biosynthesis; Histone Deacetylases/deficiency; Histone Deacetylases/genetics; Histone Deacetylases/physiology; Isoenzymes/metabolism; Mice; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; Repressor Proteins/biosynthesis; Repressor Proteins/genetics; Repressor Proteins/physiology; Signal Transduction/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:HDAC2

acts_upstream_of_or_within

GO:0051896: regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3712002

P

  • regulates_o_occurs_in:(EMAPA:16105)

Seeded From UniProt

complete

MOUSE:HDAC2

acts_upstream_of_or_within

GO:0060297: regulation of sarcomere organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3712002

P

  • regulates_o_occurs_in:(CL:0000746)
  • regulates_o_occurs_in:(EMAPA:32748)

Seeded From UniProt

complete

MOUSE:HDAC2

acts_upstream_of_or_within

GO:0060044: negative regulation of cardiac muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3712002

P

  • regulates_o_occurs_in:(EMAPA:32748)

Seeded From UniProt

complete

MOUSE:HDAC2

acts_upstream_of_or_within

GO:0055013: cardiac muscle cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3712002

P

  • occurs_in:(EMAPA:32748)

Seeded From UniProt

complete

MOUSE:HDAC2

acts_upstream_of_or_within

GO:0055013: cardiac muscle cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3712002

P

occurs_in:(EMAPA:32748)

Seeded From UniProt

complete

MOUSE:HDAC2

acts_upstream_of_or_within

GO:0051896: regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3712002

P

regulates_o_occurs_in:(EMAPA:16105)

Seeded From UniProt

complete

MOUSE:HDAC2

acts_upstream_of_or_within

GO:0060044: negative regulation of cardiac muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3712002

P

regulates_o_occurs_in:(EMAPA:32748)

Seeded From UniProt

complete

MOUSE:HDAC2

acts_upstream_of_or_within

GO:0060297: regulation of sarcomere organization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3712002

P

  • regulates_o_occurs_in:(EMAPA:32748)
  • regulates_o_occurs_in:(CL:0000746)

Seeded From UniProt

complete

See also

References

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