Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

Nature. 2019 Aug;572(7769):335-340. doi: 10.1038/s41586-019-1406-x. Epub 2019 Jul 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / pathology
  • Calcium / metabolism
  • Cardiomyopathy, Dilated / genetics*
  • Cells, Cultured
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly / genetics
  • Haploinsufficiency / genetics
  • Homeostasis
  • Humans
  • In Vitro Techniques
  • Induced Pluripotent Stem Cells / pathology
  • Lamin Type A / genetics*
  • Models, Biological
  • Mutation*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Nonsense Mediated mRNA Decay
  • Platelet-Derived Growth Factor / metabolism*
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Signal Transduction*
  • Single-Cell Analysis

Substances

  • Chromatin
  • LMNA protein, human
  • Lamin Type A
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • lamin C
  • Receptor, Platelet-Derived Growth Factor beta
  • Calcium