Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy
Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy
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DOI：
10.1038/s41586-019-1406-x
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发表时间：
2019-08-15
期刊：
影响因子：
64.8
通讯作者：
Wu, Joseph C.
中科院分区：
文献类型：
--
作者：
Lee, Jaecheol;Termglinchan, Vittavat;Wu, Joseph C.
核纤层蛋白A/C（LaminA/C，LMNA）是扩张型心肌病（dilated cardiomyopathy，DCM）最常发生突变的基因之一。与LMNA突变相关的DCM是一种常见的遗传性心肌病，与收缩功能障碍和心律失常相关。在这里，我们使用患者特异性诱导多能干细胞衍生的心肌细胞（iPSC-CM）在体外模拟了LMNA相关的DCM。电生理学研究表明，突变的iPSC-CM表现出异常的钙稳态，导致单细胞水平的心律失常。从机制上讲，我们表明，血小板源性生长因子（PDGF）信号转导通路激活突变iPSC-CM相比，同基因控制iPSC-CM。相反，PDGF信号传导途径的药理学和分子抑制改善了体外突变iPSC-CM的代谢表型。总之，我们的研究结果表明，PDGF通路的激活有助于LMNA相关DCM的发病机制，并指出PDGF受体β（PDGFRB）作为一个潜在的治疗靶点。
Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-beta (PDGFRB) as a potential therapeutic target.