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.
Anacardic acid is an alkylsalicylic acid obtained from cashew-nut-shell liquid, and is a potent inhibitor of p300 histone acetyl-transferase (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.
Davidson
Sean M
SM
Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. s.davidson@ucl.ac.uk
Townsend
Paul A
PA
Carroll
Chris
C
Yurek-George
Alexander
A
Balasubramanyam
Karanam
K
Kundu
Tapas K
TK
Stephanou
Anastasis
A
Packham
Graham
G
Ganesan
A
A
Latchman
David S
DS
D048729:Anacardic Acids / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D001483:Base Sequence; D048429:Cell Size; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D050881:E1A-Associated p300 Protein; D005260:Female; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation; D054832:Urocortins
D048729:Anacardic Acids; D009687:Nuclear Proteins; D015534:Trans-Activators; D054832:Urocortins; C088115:anacardic acid; D010656:Phenylephrine; D003346:Corticotropin-Releasing Hormone; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat