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Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3β activity

Nature Medicine volume 13, pages 324–331 (2007)Cite this article

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 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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Acknowledgements

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

Author notes

  1. Yang Luo, Zhan Yin & Maozhen Zhang

    Present address: Present addresses: Novartis Institutes of Biomedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, USA (Y.L.), Institute of Hydrobiology, Chinese Academy of Sciences, 7 Donghu South Road, Wuhan 430072, China (Z.Y.) and Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kong Jiang Road, Shanghai 200092, China (M.Z.).,

  2. Chinmay M Trivedi, Yang Luo and Zhan Yin: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Cell and Developmental Biology, 1156 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Chinmay M Trivedi, Wenting Zhu & Jonathan A Epstein

  2. Cardiovascular Institute, 956 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Chinmay M Trivedi, Yang Luo, Zhan Yin, Maozhen Zhang, Tao Wang, Victor A Ferrari, Peter J Gruber & Jonathan A Epstein

  3. Institute of Developmental Genetics, GSF National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, Neuherberg, 85764, Germany

    Thomas Floss & Wolfgang Wurst

  4. Technical University Munich and Toxicology Department of the GSF National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, Neuherberg, 85764, Germany

    Martin Goettlicher

  5. Department of Vertebrate Genomics, Max-Planck Institute for Molecular Genetics, Hessische Str. 3-4, Berlin, 10115, Germany

    Patricia Ruiz Noppinger

  6. Hematology-Oncology Division, 912 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Charles S Abrams

  7. The Cardiac Center, 905 Basic Research Building II, Children's Hospital of Philadelphia, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Peter J Gruber

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Contributions

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.

Ethics declarations

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). https://doi.org/10.1038/nm1552

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