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. Wang, Michael P. Snyder, Howard Y. Chang, Ioannis Karakikes () and Joseph C. Wu ()
Additional contact information
Jaecheol Lee: Stanford University
Vittavat Termglinchan: Stanford University
Sebastian Diecke: Berlin Institute of Health
Ilanit Itzhaki: Stanford University
Chi Keung Lam: Stanford University
Priyanka Garg: Stanford University
Edward Lau: Stanford University
Matthew Greenhaw: Stanford University School of Medicine
Timon Seeger: Stanford University
Haodi Wu: Stanford University
Joe Z. Zhang: Stanford University
Xingqi Chen: Stanford University
Isaac Perea Gil: Stanford University
Mohamed Ameen: Stanford University
Karim Sallam: Stanford University
June-Wha Rhee: Stanford University
Jared M. Churko: Stanford University
Rinkal Chaudhary: Stanford University
Tony Chour: Stanford University
Paul J. Wang: Division of Cardiovascular Medicine, Stanford University
Michael P. Snyder: Stanford University
Howard Y. Chang: Stanford University
Ioannis Karakikes: Stanford University
Joseph C. Wu: Stanford University

Nature, 2019, vol. 572, issue 7769, 335-340

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1406-x

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