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Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3β activity


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 3β (Gsk3β) 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 Gsk3β. Chemical inhibition of activated Gsk3β 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 Gsk3β are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.

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Figure 1: Inactivation of Hdac2.
Figure 2: Partial postnatal lethality and myocardial defects in Hdac2-null mice.
Figure 3: Hdac2-deficient mice are resistant to cardiac hypertrophy.
Figure 4: Transgenic overexpression of Hdac2 causes cardiac hypertrophy.
Figure 5: Hdac2 regulates a Pdk-Akt-Gsk3β pathway in the heart.
Figure 6: Gsk3β inhibition rescues resistance to cardiac hypertrophy in Hdac2-null mice.

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We thank J. Tobias for his help with microarray data analysis; A. Granger and M. Levin for assistance with cardiac myocyte isolation; K.J. Duffy for his help with analysis of echocardiography data; R. Zhou for assistance with magnetic resonance imaging; and T. Force (Thomas Jefferson University) for dnAkt and caAkt adenovirus and constructs, and for advice with the manuscript. This work was supported by the US National Institutes of Health (RO1 HL071546 to J.A.E.). J.A.E. holds the W.W. Smith Endowed Chair for Cardiovascular Research at the University of Pennsylvania. C.M.T. is supported by an American Heart Association postdoctoral fellowship.

Author information

Authors and Affiliations



C.M.T. contributed significantly to the writing of the manuscript. M.Z. performed histological sectioning of embryo and heart tissue. W.Z. assisted with siRNA experiments. T.W. performed TAC surgery. T.F., M.G., P.R.N. and W.W. created the Hdac2 gene-trap ES line. V.A.F. carried out echocardiography and MRI studies. C.S.A. helped with PI3K activity experiments and provided advice related to PI3K signaling. P.J.G. was instrumental during early stages of the project and initiated Hdac2 expression studies. J.A.E. conceived, designed and directed the study, supervised C.M.T., Y.L., Z.Y., M.Z., T.W. and W.Z., and wrote the manuscript.

Corresponding author

Correspondence to Jonathan A Epstein.

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Competing interests

Y.L. declares that he is presently employed by Novartis Pharmaceuticals, though he did not work for Novartis at the time that the work was performed in the Epstein lab. V.F. declares that he receives grant support from GlaxoSmithKline, Inc. Other authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Transgenic over-expression of Hdac1 or Hdac3 does not affect Inpp5f expression. (PDF 270 kb)

Supplementary Fig. 2

Regulation of Inpp5f expression in H9c2 myocytes. (PDF 262 kb)

Supplementary Fig. 3

Loss of Hdac2 does not affect activity of Pkc, PKA, or Ilk. (PDF 569 kb)

Supplementary Table 1

Genotypes of Hdac2+/− intercrosses. (PDF 48 kb)

Supplementary Table 2

Proliferation of myocardial cells. (PDF 49 kb)

Supplementary Table 3

Measurements of cardiac hypertrophy at P60-80. (PDF 68 kb)

Supplementary Methods (PDF 55 kb)

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Trivedi, C., Luo, Y., Yin, Z. et al. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3β activity. Nat Med 13, 324–331 (2007).

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