Wu Haodi, Lee Jaecheol, Vincent Ludovic G, Wang Qingtong, Gu Mingxia, Lan Feng, Churko Jared M, Sallam Karim I, Matsa Elena, Sharma Arun, Gold Joseph D, Engler Adam J, Xiang Yang K, Bers Donald M, Wu Joseph C
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.
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Cell Stem Cell. 2015 Jul 2;17(1):89-100. doi: 10.1016/j.stem.2015.04.020. Epub 2015 Jun 18.
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.
β-肾上腺素能信号通路介导心脏功能的关键方面。其失调与一系列心脏疾病有关，包括扩张型心肌病（DCM）。此前，我们从患有肌节蛋白TNNT2突变的患者中建立了家族性DCM的诱导多能干细胞（iPSC）模型。在此，我们发现β-肾上腺素能激动剂异丙肾上腺素在iPSC衍生的心肌细胞（iPSC-CMs）中诱导成熟的β-肾上腺素能信号，但该通路在DCM iPSC-CMs中减弱。尽管对照和DCM iPSC-CMs之间几种β-肾上腺素能信号成分的表达水平没有改变，但我们发现磷酸二酯酶（PDEs）2A和PDE3A在DCM iPSC-CMs中上调，且PDE2A在DCM患者组织中也上调。我们进一步发现，在DCM iPSC-CMs和患者组织中，突变型TNNT2的核定位增加以及PDE基因的表观遗传修饰。值得注意的是，对PDE2A和PDE3A的药理抑制恢复了cAMP水平，并改善了DCM iPSC-CMs受损的β-肾上腺素能信号，提示其具有治疗潜力。
