Epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised β-adrenergic signaling in an iPSC model of dilated cardiomyopathy
Open accessAbstract
β-adrenergic signaling pathways mediate key aspects of cardiac function. Its dysregulation is associated with a range of cardiac diseases, including dilated cardiomyopathy (DCM). Previously, we established an iPSC model of familial DCM from patients with a mutation in TNNT2, a sarcomeric protein. Here, we found that the β-adrenergic agonist isoproterenol induced mature β-adrenergic signaling in iPSC-derived cardiomyocytes (iPSC-CMs) but that this pathway was blunted in DCM iPSC-CMs. Although expression levels of several β-adrenergic signaling components were unaltered between control and DCM iPSC-CMs, we found that phosphodiesterases (PDEs) 2A and PDE3A were upregulated in DCM iPSC-CMs and that PDE2A was also upregulated in DCM patient tissue. We further discovered increased nuclear localization of mutant TNNT2 and epigenetic modifications of PDE genes in both DCM iPSC-CMs and patient tissue. Notably, pharmacologic inhibition of PDE2A and PDE3A restored cAMP levels and ameliorated the impaired β-adrenergic signaling of DCM iPSC-CMs, suggesting therapeutic potential.
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Using patient-specific hiPSC-CMs, researchers can model various CVDs such as long QT syndrome, LV non-compaction, hypertrophic cardiomyopathy, and dilated cardiomyopathy.
“In addition, using patient-specific hiPSC-CMs, researchers are able to model various CVDs such as long QT syndrome, LV non-compaction, hypertrophic cardiomyopathy and dilated cardiomyopathy [217,423,424].”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [423]
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References 44 · Cited by 177
- Authors
- Wu, H., Lee, J., Vincent, L. G., Wang, Q., Gu, M., Lan, F., Churko, J. M., Sallam, K. I., Matsa, E., Sharma, A., Gold, J. D., Engler, A. J., Xiang, Y. K., Bers, D. M., & Wu, J. C.
- Affiliations
- Stanford Medicine (US)
- University of California San Diego (US)
- University of California, Davis (US)
- Corresponding author
- Wu, Joseph C.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 17
- Issue
- 1
- Pages
- 89-100
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4546705
- OpenAlex
- W1898753515
- Cited by
- 177
- References
- 44
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 10 · 2023: 9 · 2022: 14 · 2021: 20 · 2020: 24 · 2019: 17 · 2018: 24 · 2017: 17 · 2016: 17 · 2015: 5
- FWCI
- 9.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Heart Association (R01 HL123968, R01 HL113006, R24 HL117756)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (U01HL099776, R01HL123968, R01HL030077, R01HL105242, R24HL117756, R01HL113006)
- Stanford Cardiovascular Institute, School of Medicine, Stanford University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- dilated cardiomyopathy, beta-adrenergic signaling, PDE2A, PDE3A, epigenetic regulation, isoproterenol, iPSC-derived cardiomyocytes, cAMP signaling, familial dilated cardiomyopathy
- MeSH terms
- Adrenergic beta-Agonists, Cardiomyopathy, Dilated, Cell Differentiation, Cells, Cultured, Heart Rate, Humans, Isoproterenol, Models, Cardiovascular, Mutation, Myocardial Contraction, Receptors, Adrenergic, beta, Signal Transduction, Up-Regulation, Troponin T, Myocytes, Cardiac, Epigenesis, Genetic, Mutant Proteins, Cyclic Nucleotide Phosphodiesterases, Type 2, Cyclic Nucleotide Phosphodiesterases, Type 3, Induced Pluripotent Stem Cells
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