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.