Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3bold beta 
activity

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.

doi:10.1038/nm1552

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Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3bold beta activity

Trivedi, C. M., Luo, Y., Yin, Z., Zhang, M., Zhu, W., Wang, T., et al. (2007). Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3bold beta activity. Nature Medicine, 13(3), 324-331. doi:10.1038/nm1552.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-0010-8236-1 Version Permalink: https://hdl.handle.net/11858/00-001M-0000-0010-8237-0

Genre: Journal Article

Alternative Title : Nat Med

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Trivedi, Chinmay M., Author
Luo, Yang, Author
Yin, Zhan, Author
Zhang, Maozhen, Author
Zhu, Wenting, Author
Wang, Tao, Author
Floss, Thomas, Author
Goettlicher, Martin, Author
Ruiz Noppinger, Patricia¹, Author
Wurst, Wolfgang, Author
Ferrari, Victor A., Author
Abrams, Charles S., Author
Gruber, Peter J., Author
Epstein, Jonathan A., Author

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1Max Planck Society, ou_persistent13

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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 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.

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Language(s): eng - English

Dates: Date issued: 2007-03

Publication Status: Issued

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Identifiers: eDoc: 335946
DOI: 10.1038/nm1552
URI: http://www.nature.com/nm/journal/v13/n3/pdf/nm1552.pdf

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Title: Nature Medicine

Alternative Title : Nat Med

Source Genre: Journal

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Pages: - Volume / Issue: 13 (3) Sequence Number: - Start / End Page: 324 - 331 Identifier: ISSN: 1078-8956