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Cell Stem Cell. 2015 Jul 2;17(1):89-100. doi: 10.1016/j.stem.2015.04.020. Epub 2015 Jun 18.

Epigenetic Regulation of Phosphodiesterases 2A and 3A Underlies Compromised β-Adrenergic Signaling in an iPSC Model of Dilated Cardiomyopathy.

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1
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
4
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
6
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: joewu@stanford.edu.

Abstract

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.

PMID:
26095046
PMCID:
PMC4546705
DOI:
10.1016/j.stem.2015.04.020
[Indexed for MEDLINE]
Free PMC Article

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