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

Haodi Wu, Jaecheol Lee, Ludovic G. Vincent, Qingtong Wang, Mingxia Gu, Feng Lan, Jared M. Churko, Karim I. Sallam, Elena Matsa, Arun Sharma, Joseph D. Gold, Adam J. Engler, Yang K. Xiang, Donald M. Bers, Joseph C. Wu

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

β-Adrenergic signalingpathwaysmediate 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 iPSCderived 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.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalCell Stem Cell
Volume17
Issue number1
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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