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

The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.

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

Open access

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

Open this paper in CoChat — free account Open PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1038/nature14332

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Angiotensin-neprilysin inhibition versus enalapril in heart failure
McMurray, J. J. V., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Solomon, S. D., Swedberg, K., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409077 · Cited by 6,957
Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling
Conti, M., & Beavo, J. A. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.060305.150444 · Cited by 1,219
Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction
Redfield, M. M., Chen, H. H., Borlaug, B. A., Semigran, M. J., Lee, K. L., Lewis, G. D., LeWinter, M. M., Rouleau, J. L., Bull, D. A., Mann, D. L., et al. (2013) · JAMA · doi:10.1001/jama.2013.2024 · Cited by 1,164
Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart
Zhou, B., Ma, Q., Rajagopal, S., Wu, S. M., Domian, I., Rivera-Feliciano, J., Jiang, D., von Gise, A., Ikeda, S., Chien, K. R., et al. (2008) · Nature · doi:10.1038/nature07060 · Cited by 1,019
Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy
Takimoto, E., Champion, H. C., Li, M., Belardi, D. F., Ren, S. V., Rodríguez, E. R., Bedja, D., Gabrielson, K. L., Wang, Y., & Kass, D. A. (2005) · Nature Medicine · doi:10.1038/nm1175 · Cited by 902
Self-citation
Advances in targeting cyclic nucleotide phosphodiesterases
Maurice, D. H., Ke, H., Ahmad, F., Wang, Y., Chung, J. H., & Manganiello, V. C. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4228 · Cited by 824
Low Myocardial Protein Kinase G Activity in Heart Failure With Preserved Ejection Fraction
van Heerebeek, L., Hamdani, N., Falcão‐Pires, I., Leite-Moreira, A. F., Begieneman, M. P. V., Bronzwaer, J. G. F., van der Velden, J., Stienen, G. J. M., Laarman, G. J., Somsen, G. A., et al. (2012) · Circulation · doi:10.1161/circulationaha.111.076075 · Cited by 545
Self-citation
Heart Failure With Preserved Ejection Fraction: Mechanisms, Clinical Features, and Therapies
Sharma, K., & Kass, D. A. (2014) · Circulation Research · doi:10.1161/circresaha.115.302922 · Cited by 508
Self-citation
Cardiac-Specific Deletion of Gata4 Reveals Its Requirement for Hypertrophy, Compensation, and Myocyte Viability
Oka, T., Maillet, M., Watt, A. J., Schwartz, R. J., Aronow, B. J., Duncan, S. A., & Molkentin, J. D. (2006) · Circulation Research · doi:10.1161/01.res.0000215985.18538.c4 · Cited by 424
A TRPC6-Dependent Pathway for Myofibroblast Transdifferentiation and Wound Healing In Vivo
Davis, J., Burr, A. R., Davis, G. F., Birnbaumer, L., & Molkentin, J. D. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.08.017 · Cited by 362

Show all 30 references

Sorted by citations

Items 101–200 of 357

Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation
Park, K. C., Crump, N. T., Louwman, N., Krywawych, S., Cheong, Y. J., Vendrell, I., Gill, E. K., Gunadasa-Rohling, M., Ford, K. L., Hauton, D., et al. (2023) · Nature Cardiovascular Research · doi:10.1038/s44161-023-00365-0 · Cited by 41
Cardiomyocyte Ca 2+ homeostasis as a therapeutic target in heart failure with reduced and preserved ejection fraction
Peana, D., & Domeier, T. L. (2017) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2017.03.005 · Cited by 41
Estrogen Receptor-α Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy
Fukuma, N., Takimoto, E., Ueda, K., Liu, P., Tajima, M., Otsu, Y., Kariya, T., Harada, M., Toko, H., Koga, K., et al. (2020) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2019.12.009 · Cited by 41
Self-citation
Mechanisms of Myocardial Reverse Remodelling and Its Clinical Significance: A Scientific Statement of the ESC Working Group on Myocardial Function
Falcão‐Pires, I., Ferreira, A. F., Trindade, F., Bertrand, L., Ciccarelli, M., Visco, V., Dawson, D. K., Hamdani, N., Laake, L. W. V., Lezoualc’h, F., et al. (2024) · European Journal of Heart Failure · doi:10.1002/ejhf.3264 · Cited by 47
Self-citation
CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1
Wang, B., Zeng, H., Zheng, W., Chen, C., & Wang, D. W. (2016) · Aging Cell · doi:10.1111/acel.12507 · Cited by 40
Identification of new PDE9A isoforms and how their expression and subcellular compartmentalization in the brain change across the life span
Patel, N. S., Klett, J., Pilarzyk, K., Lee, D. I., Kass, D. A., Menniti, F. S., & Kelly, M. P. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.01.019 · Cited by 40
Self-citation
The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases
Correia, S. S., Iyengar, R. R., Germano, P., Tang, K., Bernier, S. G., Schwartzkopf, C. D., Tobin, J. V., Lee, T. W.-H., Liu, G., Jacobson, S., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.656561 · Cited by 40
Hemodynamic, Hormonal, and Renal Actions of Phosphodiesterase-9 Inhibition in Experimental Heart Failure
Scott, N. J. A., Rademaker, M. T., Charles, C. J., Espiner, E. A., & Richards, M. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.05.067 · Cited by 39
β3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes
Schobesberger, S., Wright, P., Poulet, C. E., Sanchez‐Alonso, J. L., Mansfield, C. A., Friebe, A., Harding, S. E., Balligand, J., Nikolaev, V. O., & Gorelik, J. (2020) · eLife · doi:10.7554/elife.52221 · Cited by 39
Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network
Zhao, C. Y., Greenstein, J. L., & Winslow, R. L. (2016) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2016.01.004 · Cited by 37
Cardiomyocyte dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays an important role in attenuating ventricular hypertrophy and dysfunction
Xu, X. Y., Zhang, P., Kwak, D., Fassett, J. T., Yue, W., Atzler, D., Hu, X., Liu, X., Wang, H., Lu, Z., et al. (2017) · Basic Research in Cardiology · doi:10.1007/s00395-017-0644-z · Cited by 37
Cyclic nucleotide phosphodiesterases: New targets in the metabolic syndrome?
Lugnier, C., Meyer, A., Talha, S., & Gény, B. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107475 · Cited by 39
Cyclic nucleotide phosphodiesterases as drug targets
Kelly, M. P., Nikolaev, V. O., Gobejishvili, L., Lugnier, C., Heßlinger, C., Nickolaus, P., Kass, D. A., de Vasconcelos, W. P., Fischmeister, R., Brocke, S., et al. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100042 · Cited by 38
Self-citation
Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review
Mollace, V., Rosano, G. M. C., Anker, S. D., Coats, A. J. S., Seferovic, P. M., Mollace, R., Tavernese, A., Gliozzi, M., Musolino, V., Carresi, C., et al. (2021) · Nutrients · doi:10.3390/nu13010257 · Cited by 35
CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload–Induced Heart Failure
Richards, D. A., Aronovitz, M. J., Liu, P., Martin, G., Tam, K., Pande, S., Karas, R. H., Bloomfield, D. M., Mendelsohn, M. E., & Blanton, R. M. (2021) · Circulation Heart Failure · doi:10.1161/circheartfailure.120.007300 · Cited by 36
The Potential of sGC Modulators for the Treatment of Age-Related Fibrosis: A Mini-Review
Sandner, P., Berger, P., & Zenzmaier, C. (2016) · Gerontology · doi:10.1159/000450946 · Cited by 35
Sacubitril/valsartan therapeutic strategy in HFpEF: Clinical insights and perspectives
Gori, M., D’Elia, E., & Senni, M. (2018) · International Journal of Cardiology · doi:10.1016/j.ijcard.2018.06.060 · Cited by 34
A Roadmap to Successful Clinical Proteomics
Wright, I., & Eyk, J. E. V. (2016) · Clinical Chemistry · doi:10.1373/clinchem.2016.254664 · Cited by 35
Imaging of PDE2- and PDE3-Mediated cGMP-to-cAMP Cross-Talk in Cardiomyocytes
Pavlaki, N., & Nikolaev, V. O. (2018) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd5010004 · Cited by 38
Prevention of PKG-1α Oxidation Suppresses Antihypertrophic/Antifibrotic Effects From PDE5 Inhibition but not sGC Stimulation
Nakamura, T., Zhu, G., Ranek, M. J., Kokkonen-Simon, K. M., Zhang, M., Kim, G. E., Tsujita, K., & Kass, D. A. (2018) · Circulation Heart Failure · doi:10.1161/circheartfailure.117.004740 · Cited by 34
Self-citation
Identifying Patients with Atrioventricular Septal Defect in Down Syndrome Populations by Using Self-Normalizing Neural Networks and Feature Selection
Pan, X., Hu, X., Zhang, Y., Feng, K., Wang, S., Chen, L., Huang, T., & Cai, Y. (2018) · Genes · doi:10.3390/genes9040208 · Cited by 34
Cyclic nucleotide phosphodiesterases (PDEs) and endothelial function in ischaemic stroke. A review
Yasmeen, S., Akram, B. H., Hainsworth, A. H., & Kruuse, C. R. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.05.011 · Cited by 34
Potential Expanded Indications for Neprilysin Inhibitors
Riddell, E., & Vader, J. M. (2017) · Current Heart Failure Reports · doi:10.1007/s11897-017-0327-y · Cited by 32
The long and winding road of designing phosphodiesterase inhibitors for the treatment of heart failure
Nadur, N. F., de Azevedo, L. L., Caruso, L., Graebin, C. S., Lacerda, R. B., & Kümmerle, A. E. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.113123 · Cited by 33
Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine
Hiemstra, J. A., Lee, D. I., Chakir, K., Gutiérrez‐Aguilar, M., Marshall, K. D., Zgoda, P. J., Cruz-Rivera, N., Dozier, D. G., Ferguson, B. S., Heublein, D. M., et al. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.116.003277 · Cited by 32
Self-citation
Disease gene classification with metagraph representations
Ata, S. K., Fang, Y., Wu, M., Li, X., & Xiao, X. (2017) · Methods · doi:10.1016/j.ymeth.2017.06.036 · Cited by 32
Design of amino acid-based self-assembled nano-drugs for therapeutic applications
Vong, L. B., Trinh, N., & Nagasaki, Y. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.06.009 · Cited by 33
Asymptomatic Diabetic Cardiomyopathy: an Underrecognized Entity in Type 2 Diabetes
Stanton, A. M., Vaduganathan, M., Chang, L., Turchin, A., Januzzi, J. L., & Aroda, V. R. (2021) · Current Diabetes Reports · doi:10.1007/s11892-021-01407-2 · Cited by 33
cGMP Signaling in the Cardiovascular System—The Role of Compartmentation and Its Live Cell Imaging
Bork, N. I., & Nikolaev, V. O. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030801 · Cited by 33
Drug Targets for Heart Failure with Preserved Ejection Fraction: A Mechanistic Approach and Review of Contemporary Clinical Trials
Patel, R. B., & Shah, S. J. (2018) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021136 · Cited by 31
Systematic assessment of antibody selectivity in plasma based on a resource of enrichment profiles
Fredolini, C., Byström, S., Sánchez‐Rivera, L., Ioannou, M., Tamburro, D., Pontén, F., Branca, R. M., Nilsson, P., Lehtiö, J., & Schwenk, J. M. (2019) · Scientific Reports · doi:10.1038/s41598-019-43552-5 · Cited by 32
Cardiac Cyclic Nucleotide Phosphodiesterases: Roles and Therapeutic Potential in Heart Failure
Preedy, M. E. J. (2020) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-020-06959-1 · Cited by 31
Therapeutic Delivery of Pip4k2c‐Modified mRNA Attenuates Cardiac Hypertrophy and Fibrosis in the Failing Heart
Magadum, A., Singh, N., Kurian, A. A., Sharkar, M. T. K., Sultana, N., Chepurko, E., Kaur, K., Żak, M. M., Hadas, Y., Lebeche, D., et al. (2021) · Advanced Science · doi:10.1002/advs.202004661 · Cited by 30
Visualising and understanding cGMP signals in the cardiovascular system
Feil, R., Lehners, M., Stehle, D., & Feil, S. C. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15500 · Cited by 30
Activation of soluble guanylyl cyclase signalling with cinaciguat improves impaired kidney function in diabetic mice
Harloff, M., Prüschenk, S., Seifert, R., & Schlossmann, J. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15425 · Cited by 29
Advances in Cyclic Nucleotide Phosphodiesterase-Targeted PET Imaging and Drug Discovery
Sun, J., Xiao, Z., Haider, A., Gebhard, C., Xu, H., Luo, H., Zhang, H., Josephson, L., Wang, L., & Liang, S. H. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00115 · Cited by 29
The Interplay between cGMP and Calcium Signaling in Alzheimer’s Disease
Jehle, A., & Garaschuk, O. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137048 · Cited by 31
Role of PDE9 in Cognition
Dorner‐Ciossek, C., Kroker, K. S., & Rosenbrock, H. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-58811-7_9 · Cited by 29
Compartmentalized cyclic nucleotides have opposing effects on regulation of hypertrophic phospholipase Cε signaling in cardiac myocytes
Nash, C. A., Brown, L. M., Malik, S., Cheng, X., & Smrcka, A. V. (2018) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2018.06.002 · Cited by 29
Marked disparity of microRNA modulation by cGMP-selective PDE5 versus PDE9 inhibitors in heart disease
Kokkonen-Simon, K. M., Saberi, A., Nakamura, T., Ranek, M. J., Zhu, G., Bedja, D., Kühn, M., Halushka, M. K., Lee, D. I., & Kass, D. A. (2018) · JCI Insight · doi:10.1172/jci.insight.121739 · Cited by 27
Self-citation
Reversible Treatment of Pressure Overload‐Induced Left Ventricular Hypertrophy through Drd5 Nucleic Acid Delivery Mediated by Functional Polyaminoglycoside
Jiang, X., Shao, M., Liu, X., Liu, X., Zhang, X., Wang, Y., Yin, K., Wang, S., Hu, Y., José, P. A., et al. (2021) · Advanced Science · doi:10.1002/advs.202003706 · Cited by 27
Current trends and future perspectives for heart failure treatment leveraging cGMP modifiers and the practical effector PKG
Nakamura, T., & Tsujita, K. (2021) · Journal of Cardiology · doi:10.1016/j.jjcc.2021.03.004 · Cited by 29
C33(S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling
Wang, P., Li, Z.-M., Cai, S., Li, J., He, P., Huang, Y., Feng, G., Luo, H., Chen, S., & Liu, P. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.38 · Cited by 28
Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction
Chen, S., Knight, W. E., & Chen, Y. (2018) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd5020022 · Cited by 28
New drugs in preclinical and early stage clinical development in the treatment of heart failure
Tamargo, J. L., Caballero, R., & Delpón, E. (2018) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1551357 · Cited by 28
Cyclic nucleotide signalling compartmentation by PDEs in cultured vascular smooth muscle cells
Zhang, L., Bouadjel, K., Manoury, B., Vandecasteele, G., Fischmeister, R., & Leblais, V. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14651 · Cited by 28
An update of cyclic nucleotide phosphodiesterase as a target for cardiac diseases
Chen, S., & Chen, Y. (2020) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2020.1821643 · Cited by 27
Acute Hemodynamic Effects and Tolerability of Phosphodiesterase-1 Inhibition With ITI-214 in Human Systolic Heart Failure
Gilotra, N. A., DeVore, A. D., Povsic, T. J., Hays, A. G., Hahn, V. S., Agunbiade, T. A., DeLong, A., Satlin, A., Chen, R., Davis, R. E., et al. (2021) · Circulation Heart Failure · doi:10.1161/circheartfailure.120.008236 · Cited by 27
Self-citation
Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling
Riehle, C., Weatherford, E. T., Wende, A. R., Jaishy, B. P., Seei, A., McCarty, N. S., Rech, M., Shi, Q., Reddy, G. R., Kutschke, W. J., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.134920 · Cited by 26
Measurement of cGMP-generating and -degrading activities and cGMP levels in cells and tissues: Focus on FRET-based cGMP indicators
Russwurm, M., & Koesling, D. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.04.006 · Cited by 26
Phosphodiesterase 9A in Brain Regulates cGMP Signaling Independent of Nitric-Oxide
Harms, J. F., Menniti, F. S., & Schmidt, C. J. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00837 · Cited by 26
CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors
Manfra, O., Calamera, G., Froese, A., Arunthavarajah, D., Surdo, N. C., Meier, S., Melleby, A. O., Aasrum, M., Aronsen, J. M., Nikolaev, V. O., et al. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab167 · Cited by 25
Biological Assessment of the NO-Dependent Endothelial Function
Boughaleb, H., Lobysheva, I. I., Zotti, F. D., Balligand, J., & Montiel, V. (2022) · Molecules · doi:10.3390/molecules27227921 · Cited by 25
Identification of murine phosphodiesterase 5A isoforms and their functional characterization in HL‐1 cardiac cell line
Campolo, F., Zevini, A., Cardarelli, S., Monaco, L., Barbagallo, F., Pellegrini, M., Cornacchione, M., Grazia, A. D., Arcangelis, V. D., Gianfrilli, D., et al. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25880 · Cited by 25
Hyperthermia-triggered NO release based on Cu-doped polypyrrole for synergistic catalytic/gas cancer therapy
Huang, C., Tang, J., Liu, Y., Chen, T., Qi, J., Sun, S., Hao, H., Zeng, W., Zhao, J., & Wu, M. (2023) · Acta Biomaterialia · doi:10.1016/j.actbio.2023.06.002 · Cited by 24
Sex Differences in Heart Failure With Preserved Ejection Fraction Reflected by B-type Natriuretic Peptide Level
Harada, E., Mizuno, Y., Kugimiya, F., Shono, M., Maeda, H., Yano, N., & Yasue, H. (2018) · The American Journal of the Medical Sciences · doi:10.1016/j.amjms.2018.06.009 · Cited by 23
Selectivity mechanism of phosphodiesterase isoform inhibitor through in silico investigations
Huang, J., Hu, B., Xu, Z., Ye, Y., Wang, H., Wang, S., Liu, Z. L., & Wang, J. (2021) · Journal of Molecular Modeling · doi:10.1007/s00894-021-04934-7 · Cited by 24
B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction ― Relevance to Age-Related Left Ventricular Modeling in Japanese ―
Harada, E., Mizuno, Y., Kugimiya, F., Shono, M., Maeda, H., Yano, N., Kuwahara, K., & Yasue, H. (2017) · Circulation Journal · doi:10.1253/circj.cj-16-1282 · Cited by 23
Cardiac Actions of Atrial Natriuretic Peptide
Kühn, M. (2015) · Circulation Research · doi:10.1161/circresaha.115.306325 · Cited by 23
cGMP and mitochondrial K+ channels—Compartmentalized but closely connected in cardioprotection
Łukowski, R., Santos, M. C., Kuret, A., & Ruth, P. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15536 · Cited by 22
Cyclic nucleotide imaging and cardiovascular disease
Berisha, F., & Nikolaev, V. O. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.038 · Cited by 22
Multiplicity of Nitric Oxide and Natriuretic Peptide Signaling in Heart Failure
Preedy, M. E. J., Baliga, R. S., & Hobbs, A. J. (2019) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000724 · Cited by 22
Cardiac cGMP Regulation and Therapeutic Applications
Mishra, S., Chander, V., & Kass, D. A. (2024) · Hypertension · doi:10.1161/hypertensionaha.124.21709 · Cited by 21
Self-citation
The mitochondrial regulator PGC1α is induced by cGMP–PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure
Zhu, G., Ueda, K., Hashimoto, M., Zhang, M., Sasaki, M., Kariya, T., Sasaki, H., Kaludercic, N., Lee, D., Bedja, D., et al. (2021) · FEBS Letters · doi:10.1002/1873-3468.14228 · Cited by 22
Self-citation
Nitric Oxide Delivery Using Biocompatible Perfluorocarbon Microemulsion for Antibacterial Effect
Choi, M., Park, S., Park, K., Jeong, H., & Hong, J. (2019) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.9b00016 · Cited by 21
Neurocardiac regulation: from cardiac mechanisms to novel therapeutic approaches
Bardsley, E. N., & Paterson, D. J. (2018) · The Journal of Physiology · doi:10.1113/jp276962 · Cited by 21
Novel approaches to the management of chronic systolic heart failure: future directions and unanswered questions
Reddy, Y. N. V., Borlaug, B. A., O’Connor, C. M., & Gersh, B. J. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz364 · Cited by 22
Cyclic Guanosine Monophosphate and Risk of Incident Heart Failure and Other Cardiovascular Events: the ARIC Study
Zhao, D., Güallar, E., Vaidya, D. M., Ndumele, C. E., Ouyang, P., Post, W. S., Lima, J. A. C., Ying, W., Kass, D. A., Hoogeveen, R. C., et al. (2020) · Journal of the American Heart Association · doi:10.1161/jaha.119.013966 · Cited by 19
Self-citation
Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis
Wu, Y., Wang, Q., Jiang, M.-Y., Huang, Y., Zhu, Z., Han, C., Tian, Y., Zhang, B., & Luo, H. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00862 · Cited by 18
Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9
Ceddia, R. P., Liu, D., Shi, F., Crowder, M. K., Mishra, S., Kass, D. A., & Collins, S. (2021) · Diabetes · doi:10.2337/db21-0100 · Cited by 18
Self-citation
GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation
Stachowski-Doll, M. J., Papadaki, M., Martin, T. G., Ma, W., Gong, H. M., Shao, S., Shen, S., Muntu, N. A., Kumar, M., Perez, E., et al. (2022) · Circulation Research · doi:10.1161/circresaha.121.319491 · Cited by 18
Self-citation
New Therapeutics for Heart Failure: Focusing on cGMP Signaling
Mangmool, S., Duangrat, R., Parichatikanond, W., & Kurose, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612866 · Cited by 19
Cyclic nucleotide regulation of cardiac sympatho‐vagal responsiveness
Li, D., & Paterson, D. J. (2016) · The Journal of Physiology · doi:10.1113/jp271827 · Cited by 18
Rethinking of phosphodiesterase 5 inhibition: the old, the new and the perspective in human health
Paronetto, M. P., & Crescioli, C. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1461642 · Cited by 17
Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics
Kelly, E. D., Ranek, M. J., Zhang, M., Kass, D. A., & Muller, G. K. (2024) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-031524-025239 · Cited by 17
Self-citation
Compartmentalized cAMP signalling and control of cardiac rhythm
Tomek, J., & Zaccolo, M. (2023) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2022.0172 · Cited by 17
Upregulation of Myocardial and Vascular Phosphodiesterase 9A in A Model of Atherosclerotic Cardiovascular Disease
Priksz, D., Bombicz, M., Varga, B., Kurucz, A., Gesztelyi, R., Balla, J., Tóth, A., Papp, Z., Szilvássy, Z., & Juhász, B. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102882 · Cited by 17
TRPV1 is a component of the atrial natriuretic signaling complex, and using orally delivered antagonists, presents a valid therapeutic target in the longitudinal reversal and treatment of cardiac hypertrophy and heart failure
Horton, J. S., Shiraishi, T., Alfulaij, N., Small-Howard, A. L., Turner, H. C., Kurokawa, T., Mori, Y., & Stokes, A. J. (2018) · Channels · doi:10.1080/19336950.2018.1547611 · Cited by 17
The Drug Candidate BGP-15 Delays the Onset of Diastolic Dysfunction in the Goto-Kakizaki Rat Model of Diabetic Cardiomyopathy
Bombicz, M., Priksz, D., Gesztelyi, R., Kiss, R., Hollos, N., Varga, B., Németh, J., Tóth, A., Papp, Z., Szilvássy, Z., et al. (2019) · Molecules · doi:10.3390/molecules24030586 · Cited by 17
Targeting Protein Kinase G to Treat Cardiac Proteotoxicity
Oeing, C. U., Mishra, S., Dunkerly-Eyring, B. L., & Ranek, M. J. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00858 · Cited by 17
Self-citation
Prognostic and clinicopathological insights of phosphodiesterase 9A gene as novel biomarker in human colorectal cancer
Susmi, T. F., Rahman, A., Khan, M. M. R., Yasmin, F., Islam, M. S., Nasif, O., Alharbi, S. A., Batiha, G. E., & Hossain, M. U. (2021) · BMC Cancer · doi:10.1186/s12885-021-08332-3 · Cited by 17
RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity
Bardsley, E. N., Davis, H., Ajijola, O. A., Buckler, K. J., Ardell, J. L., Shivkumar, K., & Paterson, D. J. (2018) · Scientific Reports · doi:10.1038/s41598-018-26651-7 · Cited by 17
Evaluation of Phosphodiesterase 9A as a Novel Biomarker in Heart Failure with Preserved Ejection Fraction
Besler, C., Rommel, K., Kresoja, K., Mörbitz, J., Kirsten, H., Scholz, M. R., Klingel, K., Thiery, J., Burkhardt, R., Buttner, P. G., et al. (2021) · ESC Heart Failure · doi:10.1002/ehf2.13327 · Cited by 17
A big-hearted molecule
Kühn, M. (2015) · Nature · doi:10.1038/nature14373 · Cited by 16
Phosphodiesterase expression in the normal and failing heart
Li, E. A., Wang, X., Han, Y. S., & Brozovich, F. V. (2018) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2018.12.013 · Cited by 16
Toward a New Paradigm for Targeted Natriuretic Peptide Enhancement in Heart Failure
Gidlöf, O. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.650124 · Cited by 18
Multiple Avenues of Modulating the Nitric Oxide Pathway in Heart Failure Clinical Trials
Singh, P., Vijayakumar, S., Kalogeroupoulos, A., & Butler, J. (2018) · Current Heart Failure Reports · doi:10.1007/s11897-018-0383-y · Cited by 16
Constitutive protein kinase G activation exacerbates stress‐induced cardiomyopathy
Schwaerzer, G. K., Casteel, D. E., Cividini, F., Kalyanaraman, H., Zhuang, S., Gu, Y., Dalton, N. D., Peterson, K. L., DILLMANN, W. H., Boss, G. R., et al. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15530 · Cited by 15
Genome-wide association study of idiopathic hypersomnia in a Japanese population
Tanida, K., Shimada, M., Khor, S., Toyoda, H., Kato, K., Kotorii, N., Kotorii, T., Ariyoshi, Y., Kato, T., Hiejima, H., et al. (2021) · Sleep and Biological Rhythms · doi:10.1007/s41105-021-00349-2 · Cited by 16
Virtual screening and in vitro experiments highlight cannabidiol as a drug‐like phosphodiesterase 9 inhibitor
Ribaudo, G., Landucci, E., Giannangeli, M., Mazzantini, C., Maccarinelli, G., Mastinu, A., Bonini, S. A., Memo, M., Pellegrini-Giampietro, D. E., & Gianoncelli, A. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15869 · Cited by 15
Sildenafil Does Not Prevent Heart Hypertrophy and Fibrosis Induced by Cardiomyocyte Angiotensin II Type 1 Receptor Signaling
Straubinger, J., Schöttle, V., Bork, N. I., Subramanian, H., Dünnes, S., Russwurm, M., Gawaz, M., Friebe, A., Nemer, M. J., Nikolaev, V. O., et al. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.115.226092 · Cited by 15
Musclin Counteracts Skeletal Muscle Dysfunction and Exercise Intolerance in Heart Failure With Preserved Ejection Fraction
Saw, E. L., Werner, L. D., Cooper, H. L., Pimental, D. R., Zamani, P. L., Chirinos, J. A., Valero‐Muñoz, M., & Sam, F. (2025) · Circulation Heart Failure · doi:10.1161/circheartfailure.124.012350 · Cited by 15
Perfluorocarbon Nanodroplets for Dual Delivery with Ultrasound/GSH-Responsive Release of Model Drug and Passive Release of Nitric Oxide
Choi, M., Jazani, A. M., Oh, J. K., & Noh, S. M. (2022) · Polymers · doi:10.3390/polym14112240 · Cited by 14
Nitric oxide-sensing actuators for modulating structure in lipid-based liquid crystalline drug delivery systems
Liu, Q., Hu, J., Whittaker, M. R., Davis, T. P., & Boyd, B. J. (2017) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2017.08.079 · Cited by 14
From bedside to bench—meeting report of the 7th International Conference on cGMP “cGMP: generators, effectors and therapeutic implications” in Trier, Germany, from June 19th to 21st 2015
Friebe, A., Sandner, P., & Seifert, R. (2015) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-015-1176-4 · Cited by 14
Cardiac cGMP Signaling in Health and Disease: Location, Location, Location
Cuello, F., & Nikolaev, V. O. (2020) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000802 · Cited by 14
Epoxyeicosatrienoic acid: A potential therapeutic target of heart failure with preserved ejection fraction
Zhang, M., Shu, H., Chen, C., He, Z., Zhou, Z., & Wang, D. W. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113326 · Cited by 13
Self-citation
Augmentation of Natriuretic Peptide Bioactivity via Combined Inhibition of Neprilysin and Phosphodiesterase-9 in Heart Failure.
Scott, N., Prickett, T., Charles, C., Frampton, C., Richards, A., & Rademaker, M. (2022) · JACC. Heart failure · doi:10.1016/j.jchf.2022.11.006 · Cited by 12
PERK-Mediated Suppression of microRNAs by Sildenafil Improves Mitochondrial Dysfunction in Heart Failure
Shimizu, T., Taguchi, A., Higashijima, Y., Takubo, N., Kanki, Y., Urade, Y., & Wada, Y. (2020) · iScience · doi:10.1016/j.isci.2020.101410 · Cited by 13
Phosphodiesterases Expression during Murine Cardiac Development
Carvalho, T. M. D. C. S., Cardarelli, S., Giorgi, M., Lenzi, A., Isidori, A. M., & Naro, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052593 · Cited by 12

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks