The transcriptional coactivator p300 plays a critical role in the hypertrophic and protective pathways induced by phenylephrine in cardiac cells but is specific to the hypertrophic effect of urocortin

Sean M. Davidson, Paul A. Townsend, Chris Carroll, Alexander Yurek-George, Karanam Balasubramanyam, Tapas K. Kundu, Anastasis Stephanou, Graham Packham, A. Ganesan, David S. Latchman

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Anacardic acid is an alkylsalicylic acid obtained from cashew-nut-shell liquid, and is a potent inhibitor of p300 histone acetyltransferase (HAT) activity. We have used anacardic acid to prevent the induction of hypertrophy in isolated neonatal rat cardiomyocytes. Hypertrophy was detected as an increase in cell size, the rearrangement of sarcomeres into a striated pattern, and the induction of embryonic genes β-MHC and ANF. p300 inhibition was equally effective at preventing hypertrophy whether it was induced by treatment with the α1-adrenergic agonist, phenylephrine, or by treatment with urocortin, a member of the corticotrophin-releasing-factor family, which stimulates specific G protein-coupled receptors. Spiruchostatin A is a natural-product inhibitor of histone deacetylases (HDAC) similar to the depsipeptide FK228 molecule. We have recently synthesized spiruchostatin A and now show that, although HDACs act in opposition to HATs, spiruchostatin A has the same effect as anacardic acid, that is, it prevents the induction of hypertrophy in response to phenylephrine or urocortin. Pretreatment with either phenylephrine or urocortin reduced the extent of death observed after the exposure of isolated cardiomyocytes to simulated ischaemia and reoxygenation. Inhibition of p300 or HDAC activity eliminated the protection conferred by phenylephrine; however, it did not affect the protection conferred by urocortin. Therefore, it might eventually be possible to use chemical inhibitors such as these in a therapeutic setting to dissociate the protective effect and hypertrophic effect of urocortin, enhancing the survival of cardiomyocytes exposed to transient ischemia, while inhibiting the hypertrophic pathway that would otherwise be induced concurrently.
    Original languageEnglish
    Pages (from-to)162-170
    Number of pages8
    JournalChemBioChem: a European journal of chemical biology
    Volume6
    Issue number1
    DOIs
    Publication statusPublished - Jan 2005

    Keywords

    • Cardiomyocytes
    • Hypertrophy
    • Inhibitors
    • Medicinal chemistry
    • Natural products

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