Identification of intracellular signaling molecules that bind to cardiac p300 during the development of heart failure and its application to pharmacological therapy

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Hypertrophic stimuli such as hypertension initiates a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and change the pattern of gene expression. The expression of endothelin-1 in cardiac myocytes is markedly induced following pressure overload during the transition from compensated hypertrophy to decompensated heart failure. Identification of nuclear pathways that lead to this induction will provide novel pharmacological targets for heart failure. One of E1A-associated proteins, p300 plays a critical role for the induction of endothelin-1 expression in cardiac myoytes, and serves as a coactivator of hypertrophy-responsive transcriptional factors such as MEF-2 and GATA-4. A p300 protein also possesses histone acetyltransferase (HAT) activity, and is involved in hypertrophic stimuli-induced acetylation and DNA binding of GATA-4 in cardiac myocytes. We have generated transgenic mice with cardiac-specific overexpression of either wild-type p300 or mutant p300 that lose its HAT activity, and found that p300-mediated acetylation of GATA-4 is required for pathological myocyte growth with decompensated heart failure in vivo. Recently, several compounds that inhibit p300-HAT activity in vitro and in culture have been reported. One of these is a natural compound, currcumin, which inhibits histone acetylation in cultured HeLa cells and repress p300-mediated chromatin transcription. This compound repressed PE-induced hypertrophic responses such as myofibrilar organization and increase in cell size, PE-induced transactivation of the cardiac fetal genes, and PE-induced increase in the DNA binding activity of GATA-4. Thus, we identified a pharmacological agent that targets nuclear pathways for pressure overload-signaling in cardiac myocytes, and could be applied for the treatment of hypertension-induced heart failure in vivo.