DOI: 10.1073/pnas.231619298. Activated glycogen synthase-3β suppresses cardiac hypertrophy <i>in vivo</i>

Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo

10.1073/pnas.231619298

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The adult myocardium responds to a variety of pathologic stimuli by hypertrophic growth that frequently progresses to heart failure. The calcium/calmodulin-dependent protein phosphatase calcineurin is a potent transducer of hypertrophic stimuli. Calcineurin dephosphorylates members of the nuclear factor of activated T cell (NFAT) family of transcription factors, which results in their translocation to the nucleus and activation of calcium-dependent genes. Glycogen synthase kinase-3 (GSK-3) phosphorylates NFAT proteins and antagonizes the actions of calcineurin by stimulating NFAT nuclear export. To determine whether activated GSK-3 can act as an antagonist of hypertrophic signaling in the adult heart in vivo , we generated transgenic mice that express a constitutively active form of GSK-3β under control of a cardiac-specific promoter. These mice were physiologically normal under nonstressed conditions, but their ability to mount a hypertrophic response to calcineurin activation was severely impaired. Similarly, cardiac-specific expression of activated GSK-3β diminished hypertrophy in response to chronic β-adrenergic stimulation and pressure overload. These findings reveal a role for GSK-3β as an inhibitor of hypertrophic signaling in the intact myocardium and suggest that elevation of cardiac GSK-3β activity may provide clinical benefit in the treatment of pathologic hypertrophy and heart failure.

Bibliography

Antos, C. L., McKinsey, T. A., Frey, N., Kutschke, W., McAnally, J., Shelton, J. M., Richardson, J. A., Hill, J. A., & Olson, E. N. (2002). Activated glycogen synthase-3Î² suppresses cardiac hypertrophy in vivo. Proceedings of the National Academy of Sciences, 99(2), 907â912.

Authors 9

Christopher L. Antos (first)
Timothy A. McKinsey (additional)
Norbert Frey (additional)
William Kutschke (additional)
John McAnally (additional)
John M. Shelton (additional)
James A. Richardson (additional)
Joseph A. Hill (additional)
Eric N. Olson (additional)

References 47 Referenced 412

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:36 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 9:43 a.m.)
Indexed	1 week ago (Aug. 29, 2025, 6:25 a.m.)
Issued	23 years, 7 months ago (Jan. 8, 2002)
Published	23 years, 7 months ago (Jan. 8, 2002)
Published Online	23 years, 7 months ago (Jan. 8, 2002)
Published Print	23 years, 7 months ago (Jan. 22, 2002)

Funders 0

None

BibTeX

@article{Antos_2002, title={Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo}, volume={99}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.231619298}, DOI={10.1073/pnas.231619298}, number={2}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Antos, Christopher L. and McKinsey, Timothy A. and Frey, Norbert and Kutschke, William and McAnally, John and Shelton, John M. and Richardson, James A. and Hill, Joseph A. and Olson, Eric N.}, year={2002}, month=jan, pages={907–912} }

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  "abstract": "<jats:p>\n            The adult myocardium responds to a variety of pathologic stimuli by hypertrophic growth that frequently progresses to heart failure. The calcium/calmodulin-dependent protein phosphatase calcineurin is a potent transducer of hypertrophic stimuli. Calcineurin dephosphorylates members of the nuclear factor of activated T cell (NFAT) family of transcription factors, which results in their translocation to the nucleus and activation of calcium-dependent genes. Glycogen synthase kinase-3 (GSK-3) phosphorylates NFAT proteins and antagonizes the actions of calcineurin by stimulating NFAT nuclear export. To determine whether activated GSK-3 can act as an antagonist of hypertrophic signaling in the adult heart\n            <jats:italic>in vivo</jats:italic>\n            , we generated transgenic mice that express a constitutively active form of GSK-3\u03b2 under control of a cardiac-specific promoter. These mice were physiologically normal under nonstressed conditions, but their ability to mount a hypertrophic response to calcineurin activation was severely impaired. Similarly, cardiac-specific expression of activated GSK-3\u03b2 diminished hypertrophy in response to chronic \u03b2-adrenergic stimulation and pressure overload. These findings reveal a role for GSK-3\u03b2 as an inhibitor of hypertrophic signaling in the intact myocardium and suggest that elevation of cardiac GSK-3\u03b2 activity may provide clinical benefit in the treatment of pathologic hypertrophy and heart failure.\n          </jats:p>",
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