Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

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. WangMichael P. Snyder, Howard Y. Chang, Ioannis Karakikes, Joseph C. Wu

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)335-340
Number of pages6
JournalNature
Volume572
Issue number7769
DOIs
StatePublished - Aug 15 2019
Externally publishedYes

ASJC Scopus subject areas

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    Lee, J., Termglinchan, V., Diecke, S., Itzhaki, I., Lam, C. K., Garg, P., Lau, E., Greenhaw, M., Seeger, T., Wu, H., Zhang, J. Z., Chen, X., Gil, I. P., Ameen, M., Sallam, K., Rhee, J. W., Churko, J. M., Chaudhary, R., Chour, T., ... Wu, J. C. (2019). Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature, 572(7769), 335-340. https://doi.org/10.1038/s41586-019-1406-x