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          Institute: MPI für molekulare Genetik     Collection: Department of Vertebrate Genomics     Display Documents



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ID: 335108.0, MPI für molekulare Genetik / Department of Vertebrate Genomics
Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity
Authors:Trivedi, Chinmay M.; Luo, Yang; Yin, Zhan; Zhang, Maozhen; Zhu, Wenting; Wang, Tao; Floss, Thomas; Goettlicher, Martin; Ruiz Noppinger, Patricia; Wurst, Wolfgang; Ferrari, Victor A.; Abrams, Charles S.; Gruber, Peter J.; Epstein, Jonathan A.
Language:English
Date of Publication (YYYY-MM-DD):2007-03
Title of Journal:Nature Medicine
Journal Abbrev.:Nat Med
Volume:13
Issue / Number:3
Start Page:324
End Page:331
Copyright:© 2008 Nature Publishing Group
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Communicated by:Hans Lehrach
Affiliations:MPI für molekulare Genetik
External Affiliations:Department of Cell and Developmental Biology, 1156 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA;
Cardiovascular Institute, 956 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA;
Institute of Developmental Genetics, GSF National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany;
Technical University Munich and Toxicology Department of the GSF National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany;
Hematology-Oncology Division, 912 Basic Research Building II, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA;
The Cardiac Center, 905 Basic Research Building II, Children's Hospital of Philadelphia, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA;
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.).
Identifiers:ISSN:1078-8956
DOI:doi:10.1038/nm1552
URL:http://www.nature.com/nm/journal/v13/n3/pdf/nm1552...
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