Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.

Nature 2019

Lee J, Termglinchan V, Diecke S, Itzhaki I, Lam CK, Garg P, Lau E, Greenhaw M, Seeger T, Wu H, Zhang JZ, Chen X, Gil IP, Ameen M, Sallam K, Rhee JW, Churko JM, Chaudhary R, Chour T, Wang PJ, Snyder MP, Chang HY, Karakikes I, Wu JC

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.

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