Please use this identifier to cite or link to this item:
Title: The Transcriptional Coactivator P300 Plays A Critical Role In The Hypertrophic And Protective Pathways Induced By Phenylephrine On Cardiac Cells But Is Specific To The Hypertrophic Effect Of Urocortin
Authors: Davidson, Sean M
Townsend, Paul A
Carroll, Chris
Yurek-George, Alexander
Balasubramanyam, Karanam
Kundu, Tapas K
Stephanou, Anastasis
Packham, Graham
Ganesan, A
Latchman, David S
Keywords: cardiomyocytes
medicinal chemistry
natural products
Neonatal-Rat Cardiomyocytes
Creb-Binding Protein
Histone Deacetylases
Gene- Expression
Acetyltransferase Activity
Issue Date: Jan-2005
Publisher: Wiley-Blackwell
Citation: ChemBioChem 6(1), 162-170 (2005)
Abstract: Anacardic acid is an alkylsalicylic acid obtained from cashewnut-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 beta-MHC and ANF p300 inhibition was equally effective at preventing hypertrophy whether it was induced by treatment with the alpha1-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.
Description: Restricted Access
Other Identifiers: 1439-4227
Appears in Collections:Research Papers (Tapas K. Kundu)

Files in This Item:
File Description SizeFormat 
2005 ChemBioChem , 6, 162-170.pdf
  Restricted Access
237.98 kBAdobe PDFView/Open Request a copy

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.