Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and diastolic function in the heart.
Glycogen synthase kinase (GSK) 3beta is a negative regulator of stress-induced cardiomyocyte hypertrophy. It is not clear, however, if GSK-3beta plays any role in regulating normal cardiac growth and cardiac function. Herein we report that a transgenic mouse expressing wild type GSK-3beta in the heart has a dramatic impairment of normal post-natal cardiomyocyte growth as well as markedly abnormal cardiac contractile function. The most striking phenotype, however, is grossly impaired diastolic relaxation, which leads to increased filling pressures of the left ventricle and massive atrial enlargement. This is due to profoundly abnormal calcium handling, leading to an inability to normalize cytosolic [Ca2+] in diastole. The alterations in calcium handling are due at least in part to direct down-regulation of the sarcoplasmic reticulum calcium ATPase (SERCA2a) by GSK-3beta, acting at the level of the SERCA2 promoter. These studies identify GSK-3beta as a regulator of normal growth of the heart and are the first of which we are aware, to demonstrate regulation of expression of SERCA2a, a critical determinant of diastolic function, by a cytosolic signaling pathway, the activity of which is dynamically modulated. De-regulation of GSK-3beta leads to severe systolic and diastolic dysfunction and progressive heart failure. Because down-regulation of SERCA2a plays a central role in the diastolic and systolic dysfunction of patients with heart failure, these findings have potential implications for the therapy of this disorder.
Michael
Ashour
A
Boston University Medical Center and School of Medicine, Boston, MA 02118, USA.
Haq
Syed
S
Chen
Xin
X
Hsich
Eileen
E
Cui
Lei
L
Walters
Brian
B
Shao
Zhili
Z
Bhattacharya
Kausik
K
Kilter
Heiko
H
Huggins
Gordon
G
Andreucci
Michele
M
Periasamy
Muthu
M
Solomon
Robert N
RN
Liao
Ronglih
R
Patten
Richard
R
Molkentin
Jeffery D
JD
Force
Thomas
T
D000818:Animals; D002118:Calcium / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000235:genetics; D003971:Diastole / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000254:growth & development / Q000502:physiology*; D006706:Homeostasis; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000502:physiology; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013599:Systole / Q000502:physiology
D011994:Recombinant Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D000252:Calcium-Transporting ATPases; D002118:Calcium