Cardiac Hypertrophy Is Inhibited by a Local Pool of cAMP Regulated by Phosphodiesterase 2.

Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE

Publication: Baltimore, MD : Lippincott Williams & Wilkins
Original Publication: Baltimore, Md. Grune & Stratton.

Second Messenger Systems*/drug effects; Cardiomegaly/*prevention & control ; Cyclic AMP/*metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 2/*metabolism ; Myocytes, Cardiac/*enzymology; Adenoviridae/genetics ; Animals ; Animals, Newborn ; Cardiomegaly/enzymology ; Cardiomegaly/genetics ; Cardiomegaly/pathology ; Cells, Cultured ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 2/genetics ; Disease Models, Animal ; Genetic Vectors ; Male ; Membrane Microdomains/enzymology ; Mice, Inbred C57BL ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/pathology ; NFATC Transcription Factors/genetics ; NFATC Transcription Factors/metabolism ; Phosphodiesterase Inhibitors/pharmacology ; Phosphorylation ; RNA Interference ; Rats, Sprague-Dawley ; Rats, Wistar ; Time Factors ; Transduction, Genetic ; Transfection

Rationale: Chronic elevation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodeling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A signaling seems 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 signaling microdomains.
Objective: How individual cAMP microdomains affect 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 antihypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of protein kinase A isoforms, we demonstrate that the antihypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a protein kinase A type II subset, leading to phosphorylation of the nuclear factor of activated T cells.
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.
(© 2015 American Heart Association, Inc.)

RG/12/3/29423 United Kingdom British Heart Foundation; RE/13/1/30181 United Kingdom British Heart Foundation; PG/10/75/28537 United Kingdom British Heart Foundation; PG/15/5/31110 United Kingdom BHF_ British Heart Foundation; MR/J007412/1 United Kingdom MRC_ Medical Research Council

Keywords: cAMP; cyclic nucleotide; hypertrophy; phosphodiesterases 2; protein kinase A; signal transduction

0 (NFATC Transcription Factors)
0 (Phosphodiesterase Inhibitors)
E0399OZS9N (Cyclic AMP)
EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 2)
EC 3.1.4.17 (Pde2a protein, mouse)
EC 3.1.4.17 (Pde2a protein, rat)

Date Created: 20150806 Date Completed: 20151231 Latest Revision: 20220129

20240829

10.1161/CIRCRESAHA.114.305892

26243800