Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo.
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-3 beta 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 beta diminished hypertrophy in response to chronic beta-adrenergic stimulation and pressure overload. These findings reveal a role for GSK-3 beta as an inhibitor of hypertrophic signaling in the intact myocardium and suggest that elevation of cardiac GSK-3 beta activity may provide clinical benefit in the treatment of pathologic hypertrophy and heart failure.
Antos
Christopher L
CL
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
McKinsey
Timothy A
TA
Frey
Norbert
N
Kutschke
William
W
McAnally
John
J
Shelton
John M
JM
Richardson
James A
JA
Hill
Joseph A
JA
Olson
Eric N
EN
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018995:Myosin Heavy Chains / Q000235:genetics; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; D018995:Myosin Heavy Chains; D007545:Isoproterenol