Document Detail

Glycogen synthase kinase-3beta regulates post-myocardial infarction remodeling and stress-induced cardiomyocyte proliferation in vivo.
MedLine Citation:
PMID:  20360256     Owner:  NLM     Status:  MEDLINE    
RATIONALE: 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).
METHODS AND 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.
Kathleen C Woulfe; Erhe Gao; Hind Lal; David Harris; Qian Fan; Ronald Vagnozzi; Morgan DeCaul; Xiying Shang; Satish Patel; James R Woodgett; Thomas Force; Jibin Zhou
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-04-01
Journal Detail:
Title:  Circulation research     Volume:  106     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-28     Completed Date:  2010-07-07     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1635-45     Citation Subset:  IM    
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MeSH Terms
Aorta, Thoracic / pathology
Cardiomegaly / pathology
Cell Division
Gene Deletion
Glycogen Synthase Kinase 3 / deficiency,  genetics,  metabolism*
Mice, Inbred C57BL
Mice, Knockout
Myocardial Infarction / pathology*
Myocytes, Cardiac / cytology*,  pathology
Myosin Heavy Chains / genetics
Promoter Regions, Genetic
Ventricular Remodeling / physiology*
Grant Support
12858//Canadian Institutes of Health Research; 74711//Canadian Institutes of Health Research; 74711//Canadian Institutes of Health Research; HL061688/HL/NHLBI NIH HHS; MOP12858//Canadian Institutes of Health Research; R01 HL061688/HL/NHLBI NIH HHS; R01 HL061688-11/HL/NHLBI NIH HHS; R01 HL061688-12/HL/NHLBI NIH HHS; R01 HL061688-13/HL/NHLBI NIH HHS
Reg. No./Substance:
EC Synthase Kinase 3; EC Heavy Chains

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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