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Glycogen synthase kinase-3beta plays a pro-apoptotic role in beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes: Role of beta1 integrins



Glycogen synthase kinase-3beta plays a pro-apoptotic role in beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes: Role of beta1 integrins



Journal of Molecular and Cellular Cardiology 42(3): 653-661



beta-adrenergic receptor (beta-AR) stimulation induces apoptosis in adult rat ventricular myocytes (ARVM). beta 1 integrin signaling plays a protective role in beta-AR-stimulated apoptosis. Glycogen synthase kinase-3 beta (GSK-3 beta), a multifunctional serine/threonine kinase, negatively regulates cardiac hypertrophy. Here we show that beta-AR stimulation (isoproterenol; 15 min) increases tyr(216) phosphorylation and GSK-3 beta activity. Inclusion of LiCl, inhibitor of GSK-3 beta, in the reaction mix or expression of catalytically inactive GSK-3 beta (KM-GSK) inhibited beta-AR-stimulated GSK-3 beta activity. Inhibition of tyrosine kinase using genistein or chelation of intracellular Ca2+ using BAPTA-AM inhibited beta-AR-stimulated increases in tyr(216) phosphorylation and GSK-3 beta activity. Inhibition of GSK-3 beta using pharmacological inhibitors or infection with KM-GSK decreased beta-AR-stimulated cytosolic cytochrome C release and apoptosis. Expression of beta 1 integrins increased ser 9 phosphorylation and inhibited beta-AR-stimulated increase in GSK-3 beta activity. Wortmannin, inhibitor of PI3-kinase, reversed the effects of beta integrins on GSK-3 activity and apoptosis. Purified active matrix metalloproteinase-2 (MMP-2), shown to interfere with beta 1 integrin signaling, increased GSK-3 beta activity, while inhibition of MMP-2 inhibited beta-AR-stimulated increases in GSK-3 beta activity. beta-AR stimulation induced nuclear accumulation of GSK-3 beta. beta-AR stimulation (3 h) increased the expression of transcription factor Gadd153 (growth arrest- and DNA damage-inducible gene 153). These data suggest that beta-AR stimulation increases GSK-3 beta activity. Activation of GSK-3 beta plays a pro-apoptotic role in beta-AR-stimulated apoptosis via the involvement of mitochondrial death pathway. beta 1 integrins inactivate GSK-3 beta and play an anti-apoptotic role via the involvement of PI3-kinase pathway. The apoptotic effects of GSK-3 beta may be mediated, at least in part, via its nuclear localization and induction of pro-apoptotic genes, such as Gadd153.

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Accession: 049165558

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PMID: 17292911

DOI: 10.1016/j.yjmcc.2006.12.011


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