Glycogen Synthase Kinase-3β Regulates Post-Myocardial Infarction Remodeling and Stress-Induced Cardiomyocyte Proliferation In Vivo

Rationale: Numerous studies have proposed that glycogen synthase kinase (GSK)-3 beta is a central regulator of the hypertrophic response of cardiomyocytes. However, all of this work has relied on overexpression of GSK-3 beta, 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-3 beta is embryonic-lethal. Objective: This study was designed to define the role played by GSK-3 beta 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-3 beta 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-3 beta appears to play at most a minor role in the hypertrophic response to PO stress. However, GSK-3 beta does regulate post-MI remodeling because the GSK-3 beta 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-3 beta also led to increased cardiomyocyte proliferation following PO and MI. Conclusions: Deletion of GSK-3 beta protects against post-MI remodeling and promotes stress-induced cardiomyocyte proliferation in the adult heart. These studies suggest that inhibition of GSK-3 beta could be a strategy to both prevent remodeling and to promote cardiac regeneration in pathological states. (Circ Res. 2010;106:1635-1645.)