Glycogen synthase kinase-3beta regulates post-myocardial infarction remodeling and stress-induced cardiomyocyte proliferation in vivo.
BACKGROUND
Numerous studies have proposed that glycogen synthase kinase (GSK)-3beta is a central regulator of the hypertrophic response of cardiomyocytes. However, all of this work has relied on overexpression of GSK-3beta, expression of constitutively active mutants, or small molecule inhibitors with documented off-target effects. Genetic loss of function approaches have not been used in the adult mouse because germ-line deletion of GSK-3beta is embryonic-lethal.


OBJECTIVE
This study was designed to define the role played by GSK-3beta in pressure overload (PO)-induced hypertrophy and remodeling following myocardial infarction (MI).


RESULTS
We used a mouse model that allows inducible, cardiomyocyte-specific deletion of GSK-3beta in the adult knockout. Surprisingly, we find that knockout mice exposed to PO induced by thoracic aortic constriction exhibit a normal hypertrophic response. Thus, in contrast to virtually all prior published studies, GSK-3beta appears to play at most a minor role in the hypertrophic response to PO stress. However, GSK-3beta does regulate post-MI remodeling because the GSK-3beta knockouts had less left ventricular dilatation and better-preserved left ventricular function at up to 8 weeks post-MI despite demonstrating significantly more hypertrophy in the remote myocardium. Deletion of GSK-3beta also led to increased cardiomyocyte proliferation following PO and MI.


CONCLUSIONS
Deletion of GSK-3beta protects against post-MI remodeling and promotes stress-induced cardiomyocyte proliferation in the adult heart. These studies suggest that inhibition of GSK-3beta could be a strategy to both prevent remodeling and to promote cardiac regeneration in pathological states.
Woulfe
Kathleen C
KC
Center for Translational Medicine and Cardiology Division, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Gao
Erhe
E
Lal
Hind
H
Harris
David
D
Fan
Qian
Q
Vagnozzi
Ronald
R
DeCaul
Morgan
M
Shang
Xiying
X
Patel
Satish
S
Woodgett
James R
JR
Force
Thomas
T
Zhou
Jibin
J
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D006332:Cardiomegaly / Q000473:pathology; D002455:Cell Division; D005091:Exons; D017353:Gene Deletion; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic; D014661:Vasoconstriction; D020257:Ventricular Remodeling / Q000502:physiology*
D038362:Glycogen Synthase Kinase 3; D018995:Myosin Heavy Chains