Glycogen Synthase Kinase-3β Is a Negative Regulator of Cardiomyocyte Hypertrophy

Abstract

Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3β (GSK-3β), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase–dependent protein kinase that phosphorylates GSK-3β on ser 9. Using adenovirus-mediated gene transfer of GSK-3β containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3β is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3β regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3β as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.

Cardiac-specific haploinsufficiency of β-catenin attenuates cardiac hypertrophy but enhances fetal gene expression in response to aortic constriction

“…Inhibition of calcineurin by cardiac overexpression of myocyte-enriched calcineurin-interacting protein (MCIP1) enhances the expression of ANF and BNP by pressure overload despite marked attenuation of hypertrophic response [28]. GSK-3β, a key regulator of cytoplasmic β-catenin level, is inhibited by hypertrophic stimuli both in vitro and in vivo [5,29]. Adenoviral infection of an active form of GSK-3β prevents cardiac hypertrophy and ANF expression induced by Endothelin-1 and phenylephrine in cultured neonatal cardiac myocytes [5].…”

“…GSK-3β, a key regulator of cytoplasmic β-catenin level, is inhibited by hypertrophic stimuli both in vitro and in vivo [5,29]. Adenoviral infection of an active form of GSK-3β prevents cardiac hypertrophy and ANF expression induced by Endothelin-1 and phenylephrine in cultured neonatal cardiac myocytes [5]. Cardiac specific overexpression of constitutively active GSK-3β, also reduce cardiac hypertrophy mediated by calcineurin activation, pressure overload, or isoproterenol infusion [4] [5].…”

“…Adenoviral infection of an active form of GSK-3β prevents cardiac hypertrophy and ANF expression induced by Endothelin-1 and phenylephrine in cultured neonatal cardiac myocytes [5]. Cardiac specific overexpression of constitutively active GSK-3β, also reduce cardiac hypertrophy mediated by calcineurin activation, pressure overload, or isoproterenol infusion [4] [5]. Interestingly, GSK-3β enhances the effects of calcineurin on the expression of ANF and BNP, but antagonizes on the switch from α-to β-myosin heavy chains [4].…”

“…Constitutively active GSK-3β attenuates cardiac hypertrophy by phosphorylating the nuclear factor of activated T cells (NFAT) and inhibiting its nuclear translocation. Similarly, the overexpression of wild-type GSK-3β in the heart also inhibits cardiac hypertrophy [5], most likely through the reduction of cytoplasmic β-catenin levels in cardiac myocyte [6]. Interestingly, wild-type GSK-3β also inhibits postnatal physiological growth in addition to pathological hypertrophy.…”

Glycogen synthase kinase-3β plays a pro-apoptotic role in β-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes: Role of β1 integrins

“…GSK-3β is shown to play a role in cardiac myocyte hypertrophy via transcription factors such as NF-AT and GATA4 [24,25]. Transcription factor Gadd153 (Growth arrest and DNA damage-inducible gene 153; a member of C/EBP transcription factor family) is suggested to play an important role in apoptosis [26].…”