Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3β activity

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Jessup, M. & Brozena, S. Heart failure. N. Engl. J. Med. 348, 2007–2018 (2003).

    Article  Google Scholar 

  2. Schrier, R.W. & Abraham, W.T. Hormones and hemodynamics in heart failure. N. Engl. J. Med. 341, 577–585 (1999).

    Article  CAS  Google Scholar 

  3. Huss, J.M. & Kelly, D.P. Mitochondrial energy metabolism in heart failure: a question of balance. J. Clin. Invest. 115, 547–555 (2005).

    Article  CAS  Google Scholar 

  4. Hoshijima, M. & Chien, K.R. Mixed signals in heart failure: cancer rules. J. Clin. Invest. 109, 849–855 (2002).

    Article  CAS  Google Scholar 

  5. Heineke, J. & Molkentin, J.D. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 7, 589–600 (2006).

    Article  CAS  Google Scholar 

  6. Izumo, S., Nadal-Ginard, B. & Mahdavi, V. Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc. Natl. Acad. Sci. USA 85, 339–343 (1988).

    Article  CAS  Google Scholar 

  7. Wolffe, A.P. Histone deacetylase: a regulator of transcription. Science 272, 371–372 (1996).

    Article  CAS  Google Scholar 

  8. Ekwall, K. Genome-wide analysis of HDAC function. Trends Genet. 21, 608–615 (2005).

    Article  CAS  Google Scholar 

  9. Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. NY Acad. Sci. 983, 84–100 (2003).

    Article  CAS  Google Scholar 

  10. McKinsey, T.A. & Olson, E.N. Cardiac histone acetylation–therapeutic opportunities abound. Trends Genet. 20, 206–213 (2004).

    Article  CAS  Google Scholar 

  11. Zhang, C.L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002).

    Article  CAS  Google Scholar 

  12. McKinsey, T.A. & Olson, E.N. Toward transcriptional therapies for the failing heart: chemical screens to modulate genes. J. Clin. Invest. 115, 538–546 (2005).

    Article  CAS  Google Scholar 

  13. Chang, S. et al. Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol. Cell. Biol. 24, 8467–8476 (2004).

    Article  CAS  Google Scholar 

  14. Antos, C.L. et al. Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors. J. Biol. Chem. 278, 28930–28937 (2003).

    Article  CAS  Google Scholar 

  15. Kook, H. et al. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. J. Clin. Invest. 112, 863–871 (2003).

    Article  CAS  Google Scholar 

  16. Kee, H.J. et al. Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation 113, 51–59 (2006).

    Article  CAS  Google Scholar 

  17. Kong, Y. et al. Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation 113, 2579–2588 (2006).

    Article  CAS  Google Scholar 

  18. Kook, H. & Epstein, J.A. Hopping to the beat. Hop regulation of cardiac gene expression. Trends Cardiovasc. Med. 13, 261–264 (2003).

    Article  CAS  Google Scholar 

  19. Chen, F. et al. Hop is an unusual homeobox gene that modulates cardiac development. Cell 110, 713–723 (2002).

    Article  CAS  Google Scholar 

  20. Shin, C.H. et al. Modulation of cardiac growth and development by HOP, an unusual homeodomain protein. Cell 110, 725–735 (2002).

    Article  CAS  Google Scholar 

  21. Chen, C.S., Weng, S.C., Tseng, P.H., Lin, H.P. & Chen, C.S. Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J. Biol. Chem. 280, 38879–38887 (2005).

    Article  CAS  Google Scholar 

  22. Yuan, Z.L., Guan, Y.J., Chatterjee, D. & Chin, Y.E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 269–273 (2005).

    Article  CAS  Google Scholar 

  23. Choi, J.D. et al. A novel variant of Inpp5f is imprinted in brain, and its expression is correlated with differential methylation of an internal CpG island. Mol. Cell. Biol. 25, 5514–5522 (2005).

    Article  CAS  Google Scholar 

  24. Minagawa, T., Ijuin, T., Mochizuki, Y. & Takenawa, T. Identification and characterization of a sac domain-containing phosphoinositide 5-phosphatase. J. Biol. Chem. 276, 22011–22015 (2001).

    Article  CAS  Google Scholar 

  25. Dorn, G.W. II & Force, T. Protein kinase cascades in the regulation of cardiac hypertrophy. J. Clin. Invest. 115, 527–537 (2005).

    Article  CAS  Google Scholar 

  26. Haq, S. et al. Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy. J. Cell Biol. 151, 117–130 (2000).

    Article  CAS  Google Scholar 

  27. Antos, C.L. et al. Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc. Natl. Acad. Sci. USA 99, 907–912 (2002).

    Article  CAS  Google Scholar 

  28. Morisco, C. et al. The Akt-glycogen synthase kinase 3beta pathway regulates transcription of atrial natriuretic factor induced by beta-adrenergic receptor stimulation in cardiac myocytes. J. Biol. Chem. 275, 14466–14475 (2000).

    Article  CAS  Google Scholar 

  29. Hardt, S.E. & Sadoshima, J. Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. Circ. Res. 90, 1055–1063 (2002).

    Article  CAS  Google Scholar 

  30. Zhang, F., Phiel, C.J., Spece, L., Gurvich, N. & Klein, P.S. Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J. Biol. Chem. 278, 33067–33077 (2003).

    Article  CAS  Google Scholar 

  31. Bolden, J.E., Peart, M.J. & Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug. Discov. 9, 769–784 (2006).

    Article  Google Scholar 

  32. Marks, P.A., Richon, V.M., Breslow, R. & Rifkind, R.A. Histone deacetylase inhibitors as new cancer drugs. Curr. Opin. Oncol. 13, 477–483 (2001).

    Article  CAS  Google Scholar 

  33. Baldinu, P. et al. Identification of a novel candidate gene, CASC2, in a region of common allelic loss at chromosome 10q26 in human endometrial cancer. Hum. Mutat. 23, 318–326 (2004).

    Article  CAS  Google Scholar 

  34. Peiffer-Schneider, S. et al. Mapping an endometrial cancer tumor suppressor gene at 10q25 and development of a bacterial clone contig for the consensus deletion interval. Genomics 52, 9–16 (1998).

    Article  CAS  Google Scholar 

  35. Marks, P.A. & Dokmanovic, M. Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert Opin. Investig. Drugs 14, 1497–1511 (2005).

    Article  CAS  Google Scholar 

  36. Skov, S. et al. Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain a and B. Cancer Res. 65, 11136–11145 (2005).

    Article  CAS  Google Scholar 

  37. Johnson, C.A. & Turner, B.M. Histone deacetylases: complex transducers of nuclear signals. Semin. Cell Dev. Biol. 10, 179–188 (1999).

    Article  CAS  Google Scholar 

  38. Rockman, H.A. et al. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc. Natl. Acad. Sci. USA 88, 8277–8281 (1991).

    Article  CAS  Google Scholar 

  39. Zhou, R., Pickup, S., Glickson, J.D., Scott, C.H. & Ferrari, V.A. Assessment of global and regional myocardial function in the mouse using cine and tagged MRI. Magn. Reson. Med. 49, 760–764 (2003).

    Article  Google Scholar 

  40. Matsui, T. et al. Adenoviral gene transfer of activated phosphatidylinositol 3′-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 100, 2373–2379 (1999).

    Article  CAS  Google Scholar 

  41. Wang, Q. et al. Protein kinase B/Akt participates in GLUT4 translocation by insulin in L6 myoblasts. Mol. Cell. Biol. 19, 4008–4018 (1999).

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1552

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing