title: Epigenetic Regulation of Phosphodiesterases 2A and 3A Underlies Compromised β-Adrenergic Signaling in an iPSC Model of Dilated Cardiomyopathy.
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.
authors.affiliation: 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.
authors.forename: Haodi
authors.initials: H
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Jaecheol
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ludovic G
authors.initials: LG
authors.lastname: Vincent
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Qingtong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Gu
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Lan
authors.affiliation: 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.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Churko
authors.affiliation: 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.
authors.forename: Karim I
authors.initials: KI
authors.lastname: Sallam
authors.affiliation: 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.
authors.forename: Elena
authors.initials: E
authors.lastname: Matsa
authors.affiliation: 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.
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Gold
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Engler
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Yang K
authors.initials: YK
authors.lastname: Xiang
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: 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.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000235:genetics* / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008955:Models, Cardiovascular; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D020107:Troponin T / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000318:Adrenergic beta-Agonists; D050505:Mutant Proteins; D011943:Receptors, Adrenergic, beta; C545568:TNNT2 protein, human; D020107:Troponin T; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517275:PDE2A protein, human; C517287:PDE3A protein, human; D007545:Isoproterenol