Deletion of GSK-3β in vivo: Revealing the role of this signal integrator in cardiomyocyte hypertrophy and proliferation
Abstract
Numerous studies have proposed that glycogen-synthase kinase-3β (GSK-3β) is a central regulator in the response of cardiomyocytes to pressure overload, integrating inputs from multiple signaling pathways that trigger the hypertrophic response. These studies have concluded that inhibition of GSK-3β is required for hypertrophy. However, all of this work has relied on over-expression of GSK-3β, on expression of mutants that are constitutively active, or on non-selective small molecule inhibitors. Genetic loss of function approaches have not been previously employed in the adult mouse because germ-line deletion of GSK-3β leads to embryonic lethality that is due to near obliteration of the ventricular cavities secondary to marked hyperproliferation of cardiomyoblasts. Our studies employ a novel mouse model that allows inducible, cardiomyocytespecific deletion of GSK-3β in the adult mouse (KO). Surprisingly, we find that KO mice exposed to pressure overload induced by thoracic-aortic constriction (TAC) exhibit a normal hypertrophic response, whether assessed by echocardiography, heart morphometrics, or measurement of cardiomyocyte size in heart sections. These findings suggest that, in contrast to virtually all prior published studies, GSK-3β plays a minor role in the hypertrophic response to pressure overload stress. Germ-line deletion of GSK-3â indicates that this kinase regulates cardiomyocyte proliferation in development. Also, ES cells lacking GSK-3β demonstrate less cardiomyocyte differentiation in embryoid bodies. Further, conditional KO of GSK-3β in the adult heart leads to increased cardiomyocyte proliferation. Therefore, GSK-3β negatively regulates cardiomyocyte proliferation both during development and in the adult heart after pressure overload. These studies clarify the role of GSK-3β in cardiac hypertrophy as well as in proliferation.
Subject Area
Cellular biology
Recommended Citation
Woulfe, Kathleen Camille, "Deletion of GSK-3β in vivo: Revealing the role of this signal integrator in cardiomyocyte hypertrophy and proliferation" (2009). ProQuest ETD Collection - Thomas Jefferson University. AAI3390441.
https://jdc.jefferson.edu/dissertations/AAI3390441
