Epigenetic Regulation of Phosphodiesterases 2A and 3A Underlies Compromised β-Adrenergic Signaling in an iPSC Model of Dilated Cardiomyopathy.
Epigenetic Regulation of Phosphodiesterases 2A and 3A Underlies Compromised β-Adrenergic Signaling in an iPSC Model of Dilated Cardiomyopathy.
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DOI：
10.1016/j.stem.2015.04.020
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发表时间：
2015-07-02
期刊：
影响因子：
23.9
通讯作者：
Wu JC
中科院分区：
文献类型：
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作者：
Wu H;Lee J;Vincent LG;Wang Q;Gu M;Lan F;Churko JM;Sallam KI;Matsa E;Sharma A;Gold JD;Engler AJ;Xiang YK;Bers DM;Wu JC
β-肾上腺素能信号通路介导心脏功能的关键方面。它的失调与一系列心脏疾病有关，包括扩张型心肌病（DCM）。以前，我们建立了家族性DCM的iPSC模型，该模型来自具有肌节蛋白TNNT 2突变的患者。在这里，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-CM）中诱导成熟的β-肾上腺素能信号传导，但该途径在DCM iPSC-CM中被钝化。尽管几种β-肾上腺素能信号传导组分的表达水平在对照和DCM iPSC-CM之间没有改变，但我们发现磷酸二酯酶（PDE）2A和PDE 3A在DCM iPSC-CM中上调，并且PDE 2A在DCM患者组织中也上调。我们进一步发现突变TNNT 2的核定位增加以及PDE基因在DCM iPSC-CM和患者组织中的表观遗传修饰。值得注意的是，PDE 2A和PDE 3A的药理学抑制恢复了cAMP水平并改善了DCM iPSC-CM中受损的β-肾上腺素能信号传导，表明了治疗潜力。
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 (PDE) 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 in DCM iPSC-CMs, suggesting therapeutic potential.