Activated glycogen synthase-3β suppresses cardiac hypertrophy <i>in vivo</i>

TLDR

Adult myocardium undergoes hypertrophic growth in response to pathological stimuli, a process driven by calcineurin‑mediated NFAT activation that promotes calcium‑dependent gene expression, while GSK‑3β phosphorylates NFAT to counteract this signaling. To determine whether activated GSK‑3β can antagonize hypertrophic signaling in the adult heart in vivo. Transgenic mice expressing a constitutively active GSK‑3β under a cardiac‑specific promoter were generated to test this hypothesis. These mice were physiologically normal but exhibited severely impaired hypertrophic responses to calcineurin activation, β‑adrenergic stimulation, and pressure overload, indicating that increased cardiac GSK‑3β activity inhibits hypertrophic signaling and may benefit treatment of heart failure.

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.