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 3 (Gsk3) 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 Gsk3. Chemical inhibition of activated Gsk3 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 Gsk3 are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.

1. Department of Cell and Developmental Biology, 1156 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
2. Cardiovascular Institute, 956 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
3. Institute of Developmental Genetics, GSF National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
4. Technical University Munich and Toxicology Department of the GSF National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
5. Max-Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Hessische Str. 3-4, 10115 Berlin, Germany.
6. Hematology-Oncology Division, 912 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
7. The Cardiac Center, 905 Basic Research Building II, Children's Hospital of Philadelphia, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
8. 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.).
9. These authors contributed equally to the work.

Correspondence to: Jonathan A Epstein^1,2 e-mail: epsteinj@mail.med.upenn.edu

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