2019年8月15日出版的《自然》发表了一项新研究成果。来自美国斯坦福大学的Joseph C. Wu和Ioannis Karakike研究组等合作揭示PDGF通路的激活在LMNA突变与扩张型心肌病之间的联系。

研究人员使用患者特异性诱导型多能干细胞来源的心肌细胞（iPSC-CM）在体外模拟LMNA相关的DCM。电生理学研究表明，突变的iPSC-CMs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，研究人员发现与同基因对照iPSC-CM相比，血小板来源生长因子（PDGF）信号通路在突变iPSC-CM中被激活。相反，PDGF信号传导途径的药理和分子抑制改善了体外突变iPSC-CM的心律失常表型。总之，这些研究结果表明，PDGF途径的激活有助于LMNA相关DCM的发病机制，并指向PDGF受体-β（PDGFRB）作为潜在的治疗靶标。

据介绍，Lamin A/C (LMNA)是扩张型心肌病(DCM)最常见的突变基因之一。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有关。

附：英文原文

Title：Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

Author: Jaecheol Lee, Vittavat Termglinchan, Sebastian Diecke, Ilanit Itzhaki, Chi Keung Lam, Priyanka Garg, Edward Lau, Matthew Greenhaw, Timon Seeger, Haodi Wu, Joe Z. Zhang, Xingqi Chen, Isaac Perea Gil, Mohamed Ameen, Karim Sallam, June-Wha Rhee, Jared M. Churko, Rinkal Chaudhary, Tony Chour, Paul J. Wang, Michael P. Snyder, Howard Y. Chang, Ioannis Karakikes, Joseph C. Wu 

Issue&Volume: Volume 572 Issue 7769

Abstract：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-β (PDGFRB) as a potential therapeutic target.

DOI：10.1038/s41586-019-1406-x

Source：https://www.nature.com/articles/s41586-019-1406-x