Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo

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

Research output: Contribution to journalArticlepeer-review

393 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)907-912
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number2
DOIs
StatePublished - Jan 22 2002

ASJC Scopus subject areas

  • General

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