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Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease
Open accessAbstract
Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7, 8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.
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“Many technological developments have been prominent, including phospho-PTM analysis to identify PDE5A targets in heart failure therapy118”
From A high-stringency blueprint of the human proteome (2020) · cites this paper as [118]
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“Now, identification of proteoforms (e.g., genetic variations, alternatively spliced products, phosphorylation118, glycosylation119, oxidative120 and other PTMs121) allow CVD sub-classification.”
From A high-stringency blueprint of the human proteome (2020) · cites this paper as [118]
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Metadata
- Authors
- Lee, D. I., Zhu, G., Sasaki, T., Cho, G.-S., Hamdani, N., Holewinski, R., Jo, S.-H., Danner, T., Zhang, M., Rainer, P. P., Bedja, D., Kirk, J. A., Ranek, M. J., Dostmann, W. R., Kwon, C., Margulies, K. B., Van Eyk, J. E., Paulus, W. J., Takimoto, E., & Kass, D. A.
- Affiliations
- Johns Hopkins University (US)
- Tanabe Pharma Corporation (Japan) (JP)
- Amsterdam Cardiovascular Sciences (NL)
- Cedars-Sinai Medical Center (US)
- Kangwon National University (KR)
- University of Vermont (US)
- University of Pennsylvania (US)
- Corresponding author
- Kass, David A.
- ORCID
- Venue
- Nature
- Published
- 2015-03
- Volume
- 519
- Issue
- 7544
- Pages
- 472-476
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4376609
- OpenAlex
- W2020159180
- Cited by
- 353
- References
- 30
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 36 · 2023: 22 · 2022: 41 · 2021: 44 · 2020: 34 · 2019: 33 · 2018: 41 · 2017: 27 · 2016: 37 · 2015: 14
- FWCI
- 17.23
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- American Heart Association
- Pfizer
- University of Pennsylvania
- University of Connecticut
- Johns Hopkins University
- European Commission (261409)
- Fondation Leducq (HL-093432)
- Österreichischen Akademie der Wissenschaften
- National Institutes of Health (HHSN268201000032C, n01hv28180-13-0-0, HL-07227, HL089847)
- National Heart, Lung, and Blood Institute (NHLBI-HV-10-05, HL089297, R01HL093432, HL-07227, N01 HV028180, HHS-N268201000032C, R01HL119012, HL105993, HL093432, HL-119012, HL-68891, HL089847, P01HL107153, R01HL089297, R01HL089847, R01HL111198, R01HL105993, T32HL007227, R01HL068891)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- PDE9A, PDE5A, cGMP signaling, cardiac hypertrophy, heart failure, pressure overload, cardiomyocytes, protein kinase G, heart disease treatment, nitric oxide synthase, neurohormones, cardiomyopathy
- MeSH terms
- Animals, Aortic Valve Stenosis, Cyclic GMP, Cardiomegaly, Humans, Male, Mice, Inbred C57BL, Myocardium, Nitric Oxide, Phosphodiesterase Inhibitors, Pressure, Stress, Physiological, 3',5'-Cyclic-AMP Phosphodiesterases, Signal Transduction, Up-Regulation, Nitric Oxide Synthase, Muscle Cells, Natriuretic Peptides, Mice
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