Cardiac hypertrophy is inhibited by a local pool of cAMP regulated by phosphodiesterase 2

Zoccarato, A. et al. (2015) Cardiac hypertrophy is inhibited by a local pool of cAMP regulated by phosphodiesterase 2. Circulation Research, 117, pp. 707-719. (doi:10.1161/CIRCRESAHA.114.305892) (PMID:26243800)

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Abstract

Rationale: Chronic elevation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodelling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A (PKA) signalling appears to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signalling microdomains. Objective: How individual cAMP microdomains impact on cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth. Methods and Results: Using pharmacological and genetic manipulation of PDE activity we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy whereas increasing cAMP levels via PDE2 inhibition is anti-hypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of PKA isoforms we demonstrate that the anti-hypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a PKA type II subset leading to phosphorylation of the nuclear factor of activated T cells (NFAT). Conclusions: Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo and its inhibition may have therapeutic applications.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hamilton, Dr Graham and Sin, Dr Yuan Yan and Nicklin, Professor Stuart and Baillie, Professor George and Gesellchen, Dr Frank and Graham, Dr Delyth and Zaccolo, Professor Manuela and Jiang, Mr He and Stangherlin, Dr Alessandra and Surdo, Dr Nicoletta and Terrin, Ms Anna
Authors: Zoccarato, A., Surdo, N. C., Aronsen, J. M., Fields, L. A., Mancuso, L., Dodoni, G., Stangherlin, A., Livie, C., Jiang, H., Sin, Y. Y., Gesellchen, F., Terrin, A., Baillie, G. S., Nicklin, S. A., Graham, D., Szabo-Fresnais, N., Krall, J., Vandeput, F., Movsesian, M., Furlan, L., Corsetti, V., Hamilton, G. M., Lefkimmiatis, K., Sjaastad, I., and Zaccolo, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Circulation Research
Publisher:American Heart Association
ISSN:0009-7330
ISSN (Online):1524-4571|
Published Online:04 August 2015
Copyright Holders:Copyright © 2016 by American Heart Association
First Published:First published in Circulation Research 117:707-719
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
540981Quantitative analysis of cAMP dynamics in cardiac myocytes sub-compartments.Manuela ZaccoloBritish Heart Foundation (BHF)PG/10/75/28537RI NEUROSCIENCE & PSYCHOLOGY