Cited by 357Phosphodiesterase function and regulationCardiovascular Function and Risk FactorsProtein Tyrosine Phosphatases

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Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease

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Lee, Dong I., Zhu, Guangshuo, Sasaki, Takashi, Cho, Gun-Sik, Hamdani, Nazha, Holewinski, Ronald, Jo, Su-Hyun, Danner, Thomas, Zhang, Manling, Rainer, Peter P., Bedja, Djahida, Kirk, Jonathan A., Ranek, Mark J., Dostmann, Wolfgang R., Kwon, Chulan, Margulies, Kenneth B., Van Eyk, Jennifer E., Paulus, Walter J., Takimoto, Eiki, Kass, David A.·2015·Nature

DOI 10.1038/nature14332PMC PMC4376609

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Abstract

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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Hulsurkar, M. M., Ong, I., Keefe, J. A., Abu-Taha, I., Dobrev, D., & Wehrens, X. H. T. (2025) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2025.11.013 · Cited by 3
Heart failure with preserved ejection fraction
van Heerebeek, L., & Paulus, W. J. (2022) · Oxford University Press eBooks · doi:10.1093/med/9780198766223.003.0029 · Cited by 2
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Zhang, H., Ruan, P., Cong, H., Xu, L., Yang, B., Ren, T., Zhang, D., Chen, H., Hu, P., Wang, Z., et al. (2024) · Animals · doi:10.3390/ani14213159 · Cited by 1
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Li, X., Hu, Y., Zhang, F., Chen, Y., Zhou, H., Guo, D., & Zhao, Q. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/4910829 · Cited by 1
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Xu, N., Zhang, C., Lim, L. L., & Wong, A. (2018) · ACM SIGBioinformatics Record · doi:10.1145/3284959.3284961 · Cited by 1
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Zheng, H., Zheng, Y., Huang, W., Jiang, L., Liu, S., Miao, P., Zhu, N., & Cao, R. Y. (2024) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-024-10489-8 · Cited by 1
The Role of Titin Phosphorylation in Changes in Myocardial Stiffness in Cardiomyopathies
Mikhailova, G. Z., Vikhlyantsev, I. M., & Lakomkin, V. L. (2024) · Российский физиологический журнал им И М Сеченова · doi:10.31857/s0869813924030042 · Cited by 1
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Smiljić, S. (2017) · Timocki medicinski glasnik · doi:10.5937/tmg1702085s · Cited by 1
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Heineke, J., Kempf, T., & Bauersachs, J. K. (2019) · Cardiovascular medicine · doi:10.1007/978-3-319-98184-0_2 · Cited by 1
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van Heerebeek, L., & Paulus, W. J. (2020) · Elsevier eBooks · doi:10.1016/b978-0-323-60987-6.00011-9 · Cited by 1
Self-citation
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Single Serine on TSC2 Exerts Biased Control over mTORC1 Activation by ERK1/2 but Not AktPreprint
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Self-citation
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Human induced pluripotent stem cell-derived cardiomyocytes to study inflammation-induced diastolic dysfunctionPreprint
Tatekoshi, Y., Chen, C., Shapiro, J. S., Chang, H., Blancard, M., Burridge, P. W., Burridge, P. W., Feinstein, M. J., D’Aquila, R. T., Hsue, P. Y., et al. (2024) · eLife · doi:10.7554/elife.95867.1 · Cited by 1
Current and Future Therapies for Management of Systolic Heart Failure
(2015) · Journal of Cardiology & Current Research · doi:10.15406/jccr.2015.03.00093
Real time cAMP dynamics in the vicinity of phospholemman in healthy and failing cardiomyocytes
Bastug-Özel, Z. (2016) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-5793
Peroxide dependent effects in human airway epithelial cells exposed to oxidant air pollutants
Wages, P. A. (2016) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/ap27-8v21

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: Lee, Dong I.
Sasaki, Takashi
Hamdani, Nazha
Holewinski, Ronald
Jo, Su-Hyun
Zhang, Manling
Rainer, Peter P.
Bedja, Djahida
Kirk, Jonathan A.
Ranek, Mark J.
Kwon, Chulan
Margulies, Kenneth B.
Paulus, Walter J.
Takimoto, Eiki
Kass, David A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2015-03
Volume: 519
Issue: 7544
Pages: 472-476
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature14332
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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Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease

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