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

  • Author(s): Wu, H
  • Wu, H
  • Wu, H
  • Lee, J
  • Lee, J
  • Lee, J
  • Vincent, LG
  • Wang, Q
  • Gu, M
  • Gu, M
  • Gu, M
  • Lan, F
  • Lan, F
  • Lan, F
  • Churko, JM
  • Churko, JM
  • Churko, JM
  • Sallam, KI
  • Sallam, KI
  • Sallam, KI
  • Matsa, E
  • Matsa, E
  • Matsa, E
  • Sharma, A
  • Sharma, A
  • Sharma, A
  • Gold, JD
  • Engler, AJ
  • Engler, AJ
  • Xiang, YK
  • Bers, DM
  • Wu, JC
  • Wu, JC
  • Wu, JC
  • et al.
Abstract

© 2015 Elsevier Inc. 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. In this paper, Wu etal. profiled the β-adrenergic signaling properties in human iPSC-CMs and demonstrated novel epigenetic mechanisms that underlie the compromised β-adrenergic signaling in DCM, a common cause of heart failure and cardiac transplantation. These results enhance our understanding of DCM pathogenesis and may uncover new therapeutic targets.

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