Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo

• DOI: 10.1073/pnas.231619298
• Publication Date: 2002-07-26T14:36:44Z
• Authors: Christopher L. Antos; Timothy A. McKinsey; Norbert Frey; William Kutschke; John McAnally; John M. Shelton; James A. Richardson; Joseph A. Hill; Eric N. Olson
• Keywords: NFAT; Pressure overload; GSK3B

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