Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte Hypertrophy
Issued Date
2023-03-31
Resource Type
ISSN
00097330
eISSN
15244571
Scopus ID
2-s2.0-85151450783
Pubmed ID
36883446
Journal Title
Circulation Research
Volume
132
Issue
7
Start Page
828
End Page
848
Rights Holder(s)
SCOPUS
Bibliographic Citation
Circulation Research Vol.132 No.7 (2023) , 828-848
Suggested Citation
Subramaniam G., Schleicher K., Kovanich D., Zerio A., Folkmanaite M., Chao Y.C., Surdo N.C., Koschinski A., Hu J., Scholten A., Heck A.J.R., Ercu M., Sholokh A., Park K.C., Klussmann E., Meraviglia V., Bellin M., Zanivan S., Hester S., Mohammed S., Zaccolo M. Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte Hypertrophy. Circulation Research Vol.132 No.7 (2023) , 828-848. 848. doi:10.1161/CIRCRESAHA.122.321448 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/81619
Title
Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte Hypertrophy
Author's Affiliation
NIHR Oxford Biomedical Research Centre
Veneto Institute of Molecular Medicine
Utrechts Instituut voor Farmaceutische Wetenschappen
Beatson Institute for Cancer Research
Max Delbruck Center for Molecular Medicine
Consiglio Nazionale delle Ricerche
Leids Universitair Medisch Centrum
Institute of Molecular Biosciences, Mahidol University
University of Oxford Medical Sciences Division
College of Medical, Veterinary & Life Sciences
Università degli Studi di Padova
Veneto Institute of Molecular Medicine
Utrechts Instituut voor Farmaceutische Wetenschappen
Beatson Institute for Cancer Research
Max Delbruck Center for Molecular Medicine
Consiglio Nazionale delle Ricerche
Leids Universitair Medisch Centrum
Institute of Molecular Biosciences, Mahidol University
University of Oxford Medical Sciences Division
College of Medical, Veterinary & Life Sciences
Università degli Studi di Padova
Other Contributor(s)
Abstract
Background: Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac β-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing. Methods: Here, we combined an integrated phosphoproteomics approach that takes advantage of the unique role that individual PDEs play in the control of local cAMP, with network analysis to identify previously unrecognized cAMP nanodomains associated with β-adrenergic stimulation. We then validated the composition and function of one of these nanodomains using biochemical, pharmacological, and genetic approaches and cardiac myocytes from both rodents and humans. Results: We demonstrate the validity of the integrated phosphoproteomic strategy to pinpoint the location and provide critical cues to determine the function of previously unknown cAMP nanodomains. We characterize in detail one such compartment and demonstrate that the PDE3A2 isoform operates in a nuclear nanodomain that involves SMAD4 (SMAD family member 4) and HDAC-1 (histone deacetylase 1). Inhibition of PDE3 results in increased HDAC-1 phosphorylation, leading to inhibition of its deacetylase activity, derepression of gene transcription, and cardiac myocyte hypertrophic growth. Conclusions: We developed a strategy for detailed mapping of subcellular PDE-specific cAMP nanodomains. Our findings reveal a mechanism that explains the negative long-term clinical outcome observed in patients with heart failure treated with PDE3 inhibitors.