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

ABSTRACT: ?-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 ?-adrenergic agonist isoproterenol induced mature ?-adrenergic signaling in iPSC-derived cardiomyocytes (iPSC-CMs) but that this pathway was blunted in DCM iPSC-CMs. Although expression levels of several ?-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 ?-adrenergic signaling of DCM iPSC-CMs, suggesting therapeutic potential.

SUBMITTER: Wu H 

PROVIDER: S-EPMC4546705 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature