Glycogen synthase kinase-3b (GSK-3b) is a ubiquitously expressed serine/threonine kinase that has multiple functions, including cell growth death and metabolism, in many cell types. We and others have shown that GSK-3b is an important negative regulator of cardiac hypertrophy. Our preliminary results suggest that protein expression of GSK-3a is downregulated during congestive heart failure in experimental animals. However, the long-term consequence of GSK-3b downregulation in the heart is unknown, particularly in terms of cardiac phenotype and function. We also found that Serine 535 phosphorylation of a critical regulator of protein translation, eIF2Be is regulated by GSK-3b. However, the role of the downstream targets of GSK-3a in mediating growth and death responses of cardiac myocytes remains to be elucidated. Our long-term goal is to elucidate the long-term cardiac effects of GSK-3a and downstream targets of GSK-3b in the heart. Our hypotheses are: 1) The long-term inactivation/downregulation of GSK-3b causes compensatory hypertrophy and prevents cardiacmyocyte apoptosis. 2) Restoring protein expression/activity of GSK-3b during heart failure prevents compensatory hypertrophy, stimulates apoptosis, and promotes cardiac dysfunction. 3) Protein degradation of GSK-3b during heart failure is mediated by the ubiquitin/proteasome pathway. 4) elF2Be plays an important role in mediating the effect of GSK-3b upon cardiac myocyte growth and cell survival responses. In order to test these hypotheses, we will 1) examine the long-term effects of specific inhibition of GSK-3b in the heart, 2) examine the functional role of GSK-3b downregulation in the failing hearts, 3) elucidate the mechanism of downregulation GSK-3b in the failing hearts, 4) and determine the functional roles of S535 elF2Be phosphorylation by GSK-3b. We will use transgenic mouse models overexpressing either dominant negative or wild type GSK-3b, dog models of heart failure, as well as cultured cardiac myocytes with adenovirus transduction, These experiments will allow us to determine whether GSK-3b is a salutary or a detrimental molecule for the failing heart and provide us with clues as to how GSK-3b should be modulated during heart failure, which may lead to a novel treatment of heart failure. It will also provide important information regarding the molecular mechanisms of cardiac myocyte growth and death by GSK-3b.
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