Abstract 199: Targeted Deletion of Glycogen Synthase Kinase-3α(GSK-3α) vs. GSK-3β identifies unique isoform-specific effects on development and hypertrophy
Background: GSK-3 and its targets play critical roles in a wide array of processes including development and cancer. In mammalian cells there are two isoforms, α and β GSK-3α is purported to be a negative regulator of cardiac hypertrophy, but this is based solely on over-expression approaches. Virtually nothing is known of the functions of GSK-3α
Methods: We generated mice deleted for GSK-3α and β, and examined cardiac development and post-natal cardiac hypertrophy.
Results: We find that deletion of GSK-3 βleads to late embryonic lethality due to marked hyper-proliferation of cardiomyocytes, resulting in obliteration of the LV cavity. In contrast, mice deleted for GSK-3α had no developmental abnormalities, consistent with full compensation by GSK-3β for loss of GSK-3α during development. However, deletion of GSK-3α leads to post-natal cardiac hypertrophy by both echocardiography and direct morphometric measurement at 4 to 5 months of age (Table 1⇓). Although LV function by echocardiography was normal, invasive hemodynamic assessment demonstrated an abnormal response to infusion of the β-adrenergic agent, isoproteronol (Table 2⇓).
Conclusions: We demonstrate for the first time that GSK-3β is necessary for normal heart development. In contrast, GSK-3α is not, but is necessary to restrain abnormal post-natal cardiac hypertrophy. Failure to do so results in contractile dysfunction. Thus GSK-3β regulates cardiomyocyte proliferation and chamber morphogenesis in development whereas GSK-3α regulates unique facets of the post-natal cardiac growth program. These data demonstrate striking isoform-specific effects of this critically important family of kinases.