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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / metabolism*
  • Cardiomyopathy, Dilated / pathology
  • Cell Differentiation
  • Cells, Cultured
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / genetics*
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / genetics*
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Epigenesis, Genetic
  • Heart Rate / drug effects
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / pathology
  • Induced Pluripotent Stem Cells / physiology*
  • Isoproterenol / pharmacology
  • Models, Cardiovascular
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation
  • Myocardial Contraction / drug effects
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology
  • Receptors, Adrenergic, beta / metabolism*
  • Signal Transduction
  • Troponin T / genetics
  • Troponin T / metabolism
  • Up-Regulation

Substances

  • Adrenergic beta-Agonists
  • Mutant Proteins
  • Receptors, Adrenergic, beta
  • TNNT2 protein, human
  • Troponin T
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • PDE2A protein, human
  • PDE3A protein, human
  • Isoproterenol

Supplementary concepts

  • Familial dilated cardiomyopathy