The role of glycogen synthase kinase-3 and camp response element-binding protein in the induction and regulation of cardiac hypertrophy in neonatal rat ventricular myocytes
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Date
2015
DOI
Authors
Sepulveda, Sean Matthew
Version
Embargo Date
2016-07-01,2016-07-14,2016-07-14,2016-07-14,2016-07-14
OA Version
Citation
Abstract
Glycogen synthase kinase-3 (GSK3) is a ubiquitously expressed protein kinase
with key roles in controlling proliferation, differentiation and survival of a wide
variety of mammalian cells. In most cells, GSK3 is active in the absence of
growth factor signaling and acts to inhibit cell proliferation and induce apoptosis.
In cardiomyocytes, GSK3 plays a novel role as a negative regulator of cardiac
hypertrophy, and it appears that GSK3 plays a central role as an inhibitor of
cardiac hypertrophy induced by a variety of stimuli. In the present study, we
sought to further elucidate the role of GSK3 in cardiomyocyte hypertrophy by
studying the effects of inhibition of GSK3 in the absence of other hypertrophic
stimuli. By combining global expression profiling with computational predictions
and experimental analysis of transcription factor binding sites, we have identified
hypertrophy-related genes that are controlled directly by GSK3 and have found
that CREB is a major transcriptional target of GSK3 in cardiomyocytes. In
addition, we find that inhibition of GSK3 is sufficient to induce the re-expression
of fetal development genes characteristic of hypertrophy, but not sufficient to
induce the full hypertrophic phenotype of cardiomyocyte growth.