Role of PDE4 Family in Cardiomyocyte Physiology and Heart Failure
Phosphodiesterase 4 (PDE4) is a key regulator of cyclic adenosine monophosphate (cAMP) signalling in cardiomyocytes, controlling contractility, calcium handling, and hypertrophic responses. PDE4 provides spatial and temporal precision to cAMP signalling, particularly under β-adrenergic stimulation,...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-03-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/6/460 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850205664612188160 |
|---|---|
| author | Ivan Sherstnev Aleksandra Judina Giovanni Battista Luciani Alessandra Ghigo Emilio Hirsch Julia Gorelik |
| author_facet | Ivan Sherstnev Aleksandra Judina Giovanni Battista Luciani Alessandra Ghigo Emilio Hirsch Julia Gorelik |
| author_sort | Ivan Sherstnev |
| collection | DOAJ |
| description | Phosphodiesterase 4 (PDE4) is a key regulator of cyclic adenosine monophosphate (cAMP) signalling in cardiomyocytes, controlling contractility, calcium handling, and hypertrophic responses. PDE4 provides spatial and temporal precision to cAMP signalling, particularly under β-adrenergic stimulation, through its compartmentalised activity in subcellular nanodomains, including the sarcoplasmic reticulum, plasma membrane and nuclear envelope. This review highlights the cardiac PDE4 isoforms PDE4A, PDE4B and PDE4D, focusing on their distinct localisation and contributions to cardiac physiology and pathophysiology, particularly in heart failure and arrhythmias. Although PDE4 plays a smaller role in overall cAMP hydrolysis in human hearts than in rodents, its compartmentalised function remains critical. Recent therapeutic advances have shifted from pan-PDE4 inhibitors to isoform-specific approaches to enhance efficacy while minimising systemic toxicity. We discuss the potential of selective PDE4 modulators, gene therapies and combination strategies in restoring cAMP compartmentation and preventing maladaptive cardiac remodelling. By integrating rodent and human studies, this review underscores the translational challenges and therapeutic opportunities surrounding PDE4, positioning it as both a key regulator of cardiac signalling and a promising target for heart failure therapies. |
| format | Article |
| id | doaj-art-d4e939a2b56042d1be48c2ac32221cdf |
| institution | OA Journals |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-d4e939a2b56042d1be48c2ac32221cdf2025-08-20T02:11:01ZengMDPI AGCells2073-44092025-03-0114646010.3390/cells14060460Role of PDE4 Family in Cardiomyocyte Physiology and Heart FailureIvan Sherstnev0Aleksandra Judina1Giovanni Battista Luciani2Alessandra Ghigo3Emilio Hirsch4Julia Gorelik5Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKCardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKDepartment of Surgery, Dentistry, Pediatrics and Gynecology, Division of Cardiac Surgery, University of Verona, 37126 Verona, ItalyDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center “Guido Tarone”, University of Torino, 10126 Torino, ItalyDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center “Guido Tarone”, University of Torino, 10126 Torino, ItalyCardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKPhosphodiesterase 4 (PDE4) is a key regulator of cyclic adenosine monophosphate (cAMP) signalling in cardiomyocytes, controlling contractility, calcium handling, and hypertrophic responses. PDE4 provides spatial and temporal precision to cAMP signalling, particularly under β-adrenergic stimulation, through its compartmentalised activity in subcellular nanodomains, including the sarcoplasmic reticulum, plasma membrane and nuclear envelope. This review highlights the cardiac PDE4 isoforms PDE4A, PDE4B and PDE4D, focusing on their distinct localisation and contributions to cardiac physiology and pathophysiology, particularly in heart failure and arrhythmias. Although PDE4 plays a smaller role in overall cAMP hydrolysis in human hearts than in rodents, its compartmentalised function remains critical. Recent therapeutic advances have shifted from pan-PDE4 inhibitors to isoform-specific approaches to enhance efficacy while minimising systemic toxicity. We discuss the potential of selective PDE4 modulators, gene therapies and combination strategies in restoring cAMP compartmentation and preventing maladaptive cardiac remodelling. By integrating rodent and human studies, this review underscores the translational challenges and therapeutic opportunities surrounding PDE4, positioning it as both a key regulator of cardiac signalling and a promising target for heart failure therapies.https://www.mdpi.com/2073-4409/14/6/460Phosphodiesterase 4cAMP signallingcardiomyocyteβ-adrenergic signallingarrhythmiacAMP compartmentation |
| spellingShingle | Ivan Sherstnev Aleksandra Judina Giovanni Battista Luciani Alessandra Ghigo Emilio Hirsch Julia Gorelik Role of PDE4 Family in Cardiomyocyte Physiology and Heart Failure Cells Phosphodiesterase 4 cAMP signalling cardiomyocyte β-adrenergic signalling arrhythmia cAMP compartmentation |
| title | Role of PDE4 Family in Cardiomyocyte Physiology and Heart Failure |
| title_full | Role of PDE4 Family in Cardiomyocyte Physiology and Heart Failure |
| title_fullStr | Role of PDE4 Family in Cardiomyocyte Physiology and Heart Failure |
| title_full_unstemmed | Role of PDE4 Family in Cardiomyocyte Physiology and Heart Failure |
| title_short | Role of PDE4 Family in Cardiomyocyte Physiology and Heart Failure |
| title_sort | role of pde4 family in cardiomyocyte physiology and heart failure |
| topic | Phosphodiesterase 4 cAMP signalling cardiomyocyte β-adrenergic signalling arrhythmia cAMP compartmentation |
| url | https://www.mdpi.com/2073-4409/14/6/460 |
| work_keys_str_mv | AT ivansherstnev roleofpde4familyincardiomyocytephysiologyandheartfailure AT aleksandrajudina roleofpde4familyincardiomyocytephysiologyandheartfailure AT giovannibattistaluciani roleofpde4familyincardiomyocytephysiologyandheartfailure AT alessandraghigo roleofpde4familyincardiomyocytephysiologyandheartfailure AT emiliohirsch roleofpde4familyincardiomyocytephysiologyandheartfailure AT juliagorelik roleofpde4familyincardiomyocytephysiologyandheartfailure |