Hypertrophy of the adult myocardium is associated with reactivation of a fetal program of cardiac gene expression. Several recent studies have documented the roles of MAP kinases, protein kinase C (PKC), calmodulin-dependent (CaM) kinases, and calcium signaling in initiating the hypertrophic response in cultured cardiomyocytes, but it is unclear how these signaling pathways are coupled to changes in cardiac gene expression. The transcription factors GATA-4 and MEF2 are important regulators of cardiac gene expression and recent studies by the investigators and others have implicated these factors as targets for the signaling pathways that induce cardiac hypertrophy. It has been shown that activation of the calcium-dependent phosphatase calcineurin induces cardiomyocyte hypertrophy in vivo and in vitro. Calcineurin dephosphorylates the transcription factor NFAT3, resulting in the translocation of NFAT3 to the nucleus its interaction with GATA-4, and the synergistic activation of hypertrophic-responsive genes. Calcineurin has also been shown to synergize with PKC and CaM kinase IV to activate the transcription of MEF2-responsive genes, but the mechanism involved has not been defined. The recent finding that members of the MEF2 family are transcriptionally activated in response to phosphorylation by MAP kinases also suggests a potential mechanism for linking hypertrophic signaling with cardiac gene regulation. The overall goal of this project is to define the role of MEF2 in cardiac hypertrophy and to characterize several transgenic mouse models of hypertrophy and heart failure in which MEF2 and NFAT have been activated in response to calcium-dependent signaling pathways.
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