Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.

Publication Year: 
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
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Public Summary: 
Scientific 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-beta (PDGFRB) as a potential therapeutic target.