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

Academic Article


  • RATIONALE: Numerous studies have proposed that glycogen synthase kinase (GSK)-3β is a central regulator of the hypertrophic response of cardiomyocytes. However, all of this work has relied on overexpression of GSK-3β, 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-3β is embryonic-lethal. OBJECTIVE: This study was designed to define the role played by GSK-3β 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-3β 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-3β appears to play at most a minor role in the hypertrophic response to PO stress. However, GSK-3β does regulate post-MI remodeling because the GSK-3β 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-3β also led to increased cardiomyocyte proliferation following PO and MI. CONCLUSIONS: Deletion of GSK-3β protects against post-MI remodeling and promotes stress-induced cardiomyocyte proliferation in the adult heart. These studies suggest that inhibition of GSK-3β could be a strategy to both prevent remodeling and to promote cardiac regeneration in pathological states. © 2010 American Heart Association, Inc.
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    Author List

  • Woulfe KC; Gao E; Lal H; Harris D; Fan Q; Vagnozzi R; Decaul M; Shang X; Patel S; Woodgett JR
  • Start Page

  • 1635
  • End Page

  • 1645
  • Volume

  • 106
  • Issue

  • 10