title: Distinct roles of GSK-3alpha and GSK-3beta phosphorylation in the heart under pressure overload.
abstract: Glycogen synthase kinase-3 (GSK-3) is a master regulator of growth and death in cardiac myocytes. GSK-3 is inactivated by hypertrophic stimuli through phosphorylation-dependent and -independent mechanisms. Inactivation of GSK-3 removes the negative constraint of GSK-3 on hypertrophy, thereby stimulating cardiac hypertrophy. N-terminal phosphorylation of the GSK-3 isoforms GSK-3alpha and GSK-3beta by upstream kinases (e.g., Akt) is a major mechanism of GSK-3 inhibition. Nonetheless, its role in mediating cardiac hypertrophy and failure remains to be established. Here we evaluated the role of Serine(S)21 and S9 phosphorylation of GSK-3alpha and GSK-3beta in the regulation of cardiac hypertrophy and function during pressure overload (PO), using GSK-3alpha S21A knock-in (alphaKI) and GSK-3beta S9A knock-in (betaKI) mice. Although inhibition of S9 phosphorylation during PO in the betaKI mice attenuated hypertrophy and heart failure (HF), inhibition of S21 phosphorylation in the alphaKI mice unexpectedly promoted hypertrophy and HF. Inhibition of S21 phosphorylation in GSK-3alpha, but not of S9 phosphorylation in GSK-3beta, caused phosphorylation and down-regulation of G1-cyclins, due to preferential localization of GSK-3alpha in the nucleus, and suppressed E2F and markers of cell proliferation, including phosphorylated histone H3, under PO, thereby contributing to decreases in the total number of myocytes in the heart. Restoration of the E2F activity by injection of adenovirus harboring cyclin D1 with a nuclear localization signal attenuated HF under PO in the alphaKI mice. Collectively, our results reveal that whereas S9 phosphorylation of GSK-3beta mediates pathological hypertrophy, S21 phosphorylation of GSK-3alpha plays a compensatory role during PO, in part by alleviating the negative constraint on the cell cycle machinery in cardiac myocytes.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Matsuda
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Chull
authors.initials: C
authors.lastname: Hong
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Goto
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takagi
authors.forename: Mimi
authors.initials: M
authors.lastname: Tamamori-Adachi
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Kitajima
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D055879:Gene Knock-In Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics
chemical_list: C530105:Ccnd1 protein, mouse; C534703:Ccng1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D050684:E2F Transcription Factors; D006657:Histones; D019938:Cyclin D1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha