Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

J Lee, V Termglinchan, S Diecke, I Itzhaki, CK Lam… - Nature, 2019 - nature.com
J Lee, V Termglinchan, S Diecke, I Itzhaki, CK Lam, P Garg, E Lau, M Greenhaw, T Seeger
Nature, 2019nature.com
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 …
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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