GSK-3alpha directly regulates beta-adrenergic  signaling and the response of the heart  to hemodynamic stress in mice.
The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, alpha and beta. Although GSK-3beta has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3alpha in the mouse heart using gene targeting. Gsk3a(-/-) mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. Surprisingly, markedly impaired beta-adrenergic responsiveness was found at both the organ and cellular level. This phenotype was reproduced by acute treatment of WT cardiomyocytes with a small molecule GSK-3 inhibitor, confirming that the response was not due to a chronic adaptation to LV dysfunction. Thus, GSK-3alpha appears to be the central regulator of a striking range of essential processes, including acute and direct positive regulation of beta-adrenergic responsiveness. In the absence of GSK-3alpha, the heart cannot respond effectively to hemodynamic stress and rapidly fails. Our findings identify what we believe to be a new paradigm of regulation of beta-adrenergic signaling and raise concerns given the rapid expansion of drug development targeting GSK-3.
Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Jibin
J
Zhou
Hind
H
Lal
Xiongwen
X
Chen
Xiying
X
Shang
Jianliang
J
Song
Yingxin
Y
Li
Risto
R
Kerkela
Bradley W
BW
Doble
Katrina
K
MacAulay
Morgan
M
DeCaul
Walter J
WJ
Koch
John
J
Farber
James
J
Woodgett
Erhe
E
Gao
Thomas
T
Force
D018663:Adrenergic Agents; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000254:growth & development*; D006439:Hemodynamics / Q000235:genetics; D006984:Hypertrophy / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D009638:Norepinephrine / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D018663:Adrenergic Agents; D020033:Protein Isoforms; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D009638:Norepinephrine