title: Deletion of GSK-3beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation.
abstract: Based on extensive preclinical data, glycogen synthase kinase-3 (GSK-3) has been proposed to be a viable drug target for a wide variety of disease states, ranging from diabetes to bipolar disorder. Since these new drugs, which will be more powerful GSK-3 inhibitors than lithium, may potentially be given to women of childbearing potential, and since it has controversially been suggested that lithium therapy might be linked to congenital cardiac defects, we asked whether GSK-3 family members are required for normal heart development in mice. We report that terminal cardiomyocyte differentiation was substantially blunted in Gsk3b(-/-) embryoid bodies. While GSK-3alpha-deficient mice were born without a cardiac phenotype, no live-born Gsk3b(-/-) pups were recovered. The Gsk3b(-/-) embryos had a double outlet RV, ventricular septal defects, and hypertrophic myopathy, with near obliteration of the ventricular cavities. The hypertrophic myopathy was caused by cardiomyocyte hyperproliferation without hypertrophy and was associated with increased expression and nuclear localization of three regulators of proliferation - GATA4, cyclin D1, and c-Myc. These studies, which we believe are the first in mammals to examine the role of GSK-3alpha and GSK-3beta in the heart using loss-of-function approaches, implicate GSK-3beta as a central regulator of embryonic cardiomyocyte proliferation and differentiation, as well as of outflow tract development. Although controversy over the teratogenic effects of lithium remains, our studies suggest that caution should be exercised in the use of newer, more potent drugs targeting GSK-3 in women of childbearing age.
authors.affiliation: Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkela
authors.forename: Lisa
authors.initials: L
authors.lastname: Kockeritz
authors.forename: Katrina
authors.initials: K
authors.lastname: Macaulay
authors.forename: Jibin
authors.initials: J
authors.lastname: Zhou
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Doble
authors.forename: Cara
authors.initials: C
authors.lastname: Beahm
authors.forename: Sarah
authors.initials: S
authors.lastname: Greytak
authors.forename: Kathleen
authors.initials: K
authors.lastname: Woulfe
authors.forename: Chinmay M
authors.initials: CM
authors.lastname: Trivedi
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Huggins
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D048429:Cell Size; D004622:Embryo, Mammalian; D017353:Gene Deletion; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D018345:Mice, Knockout; D032386:Myoblasts, Cardiac / Q000502:physiology*
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3