Identification of Nuclear Signaling Pathways That Lead to the Development of Heart Failure

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The purpose of the present study is to identify nuclear signaling pathways that lead to the development of heart failure. Our previous studies demonstrate that a cardiac zinc finger protein GATA-4 is one of the transcriptional factors that regulate hypertrophic responses in cardiac myocytes. The full transcriptional activity of GATA-4 requires its interaction with an adenovirus associated protein, p300. A p300 protein is one, of intrinsic histone acetyltransferases (HAT) and governs gene expression patterns by being recruited to target genes through association with specific transcription factors. HAT activity of p300 is required for acetylating a subset of transcription factors as well as promoting a transcriptionally active chromatin configuration. We show here that p300,is involved in hypertrophic stimuli-induced acetylation and DNA binding of GATA-4 in cardiac myocytes. In addition, we demonstrate that cardiac overexpression of p300 promotes LV remodeling following MI in adult mice in vivo and that HAT activity of p300 is required for these processes. The findings suggest that pharmacological inhibition of p300/GATA-4 transcriptional pathway could be a novel strategy for the treatment of decompensated heart failure in vivo.