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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 (in special Issue on EMBO Symposium: Chemistry Meets Biology)

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 (in special Issue on EMBO Symposium: Chemistry Meets Biology)
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 (in special Issue on EMBO Symposium: Chemistry Meets Biology)
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 ?-MHC and ANF. p300 inhibition was equally effective at preventing hypertrophy whether it was induced by treatment with the ?1-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.
cardiomyocytes, hypertrophy, inhibitors, medicinal chemistry, natural products
1439-4227
162-170
Davidson, Sean M.
b8eeed87-5d86-42ca-8844-25bf6887253c
Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Carroll, Chris
480b8a5a-f29f-472e-b3da-6df6bc8752ff
Yurek-George, Alexander
bf3e1ac0-1459-4c95-93da-d7adba966f39
Balasubramanyam, Karanam
97acc756-c961-4f43-a938-b8979af7ef86
Kundu, Tapas K.
b1e70f8b-641e-43d4-bf5c-fcc624829e4e
Stephanou, Anastasis
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Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Ganesan, A.
62aa5a87-9308-4383-8686-99726b6bcfb9
Latchman, David S.
71e9db7c-9075-4b49-afac-6413085378db
Davidson, Sean M.
b8eeed87-5d86-42ca-8844-25bf6887253c
Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Carroll, Chris
480b8a5a-f29f-472e-b3da-6df6bc8752ff
Yurek-George, Alexander
bf3e1ac0-1459-4c95-93da-d7adba966f39
Balasubramanyam, Karanam
97acc756-c961-4f43-a938-b8979af7ef86
Kundu, Tapas K.
b1e70f8b-641e-43d4-bf5c-fcc624829e4e
Stephanou, Anastasis
e9d502e8-693c-4458-a3c6-5e2844665db3
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Ganesan, A.
62aa5a87-9308-4383-8686-99726b6bcfb9
Latchman, David S.
71e9db7c-9075-4b49-afac-6413085378db

Davidson, Sean M., Townsend, Paul A., Carroll, Chris, Yurek-George, Alexander, Balasubramanyam, Karanam, Kundu, Tapas K., Stephanou, Anastasis, Packham, Graham, Ganesan, A. and Latchman, David S. (2005) 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 (in special Issue on EMBO Symposium: Chemistry Meets Biology). ChemBioChem, 6 (1), 162-170. (doi:10.1002/cbic.200400246).

Record type: Article

Abstract

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 ?-MHC and ANF. p300 inhibition was equally effective at preventing hypertrophy whether it was induced by treatment with the ?1-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.

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Published date: 2005
Additional Information: Special issue edited by Orlando Schärer and Carsten Schultz
Keywords: cardiomyocytes, hypertrophy, inhibitors, medicinal chemistry, natural products

Identifiers

Local EPrints ID: 24674
URI: http://eprints.soton.ac.uk/id/eprint/24674
ISSN: 1439-4227
PURE UUID: cda9f208-f037-4228-96c1-dae3dbe23df8
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 03 Apr 2006
Last modified: 19 Nov 2019 01:52

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Contributors

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

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