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Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

Item Type:Article
Title:Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy
Creators Name:Lee, J. and Termglinchan, V. and Diecke, S. and Itzhaki, I. and Lam, C.K. and Garg, P. and Lau, E. and Greenhaw, M. and Seeger, T. and Wu, H. and Zhang, J.Z and Chen, X. and Gil, I.P. and Ameen, M. and Sallam, K. and Rhee, J.W. and Churko, J.M. and Chaudhary, R. and Chour, T. and Wang, P.J. and Snyder, M.P. and Chang, H.Y. and Karakikes, I. and Wu, J.C.
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.
Keywords:Biological Models, Calcium, Cardiac Arrhythmias, Cardiac Myocytes, Chromatin, Chromatin Assembly and Disassembly, Cultured Cells, Dilated Cardiomyopathy, Haploinsufficiency, Homeostasis, In Vitro Techniques, Induced Pluripotent Stem Cells, Lamin Type A, Messenger RNA, Mutation, Nonsense Mediated mRNA Decay, Platelet-Derived Growth Factor, Platelet-Derived Growth Factor beta Receptor, Signal Transduction, Single-Cell Analysis
Publisher:Nature Publishing Group
Page Range:335-340
Date:15 August 2019
Official Publication:https://doi.org/10.1038/s41586-019-1406-x
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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