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

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.