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Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.

  • Author(s): Lee, Jaecheol;
  • Termglinchan, Vittavat;
  • Diecke, Sebastian;
  • Itzhaki, Ilanit;
  • Lam, Chi Keung;
  • Garg, Priyanka;
  • Lau, Edward;
  • Greenhaw, Matthew;
  • Seeger, Timon;
  • Wu, Haodi;
  • Zhang, Joe Z;
  • Chen, Xingqi;
  • Gil, Isaac Perea;
  • Ameen, Mohamed;
  • Sallam, Karim;
  • Rhee, June-Wha;
  • Churko, Jared M;
  • Chaudhary, Rinkal;
  • Chour, Tony;
  • Wang, Paul J;
  • Snyder, Michael P;
  • Chang, Howard Y;
  • Karakikes, Ioannis;
  • Wu, Joseph C
  • et al.
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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