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Glycogen synthase kinase-3beta regulates post-myocardial infarction remodeling and stress-induced cardiomyocyte proliferation in vivo.


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

SUBMITTER: Woulfe KC 

PROVIDER: S-EPMC2895414 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Glycogen synthase kinase-3beta regulates post-myocardial infarction remodeling and stress-induced cardiomyocyte proliferation in vivo.

Woulfe Kathleen C KC   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  

Circulation research 20100401 10


<h4>Rationale</h4>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.<h4>Objective</h4>This st  ...[more]

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