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Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy

Jaecheol Lee1,2,3,4, Vittavat Termglinchan5,6,7, Sebastian Diecke8,9,10

  • 1Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. jaecheol@skku.edu.

Nature
|July 19, 2019
PubMed

Insights

Mutations in the Lamin A/C (LMNA) gene cause dilated cardiomyopathy (DCM). Targeting the platelet-derived growth factor (PDGF) pathway may treat this inherited heart condition.

Area of Science:

  • Cardiovascular Biology
  • Stem Cell Biology
  • Genetics

Background:

  • Mutations in the Lamin A/C (LMNA) gene are a frequent cause of inherited dilated cardiomyopathy (DCM).
  • LMNA-related DCM is characterized by impaired systolic function and cardiac arrhythmias.
  • Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a model for studying disease mechanisms.

Purpose of the Study:

  • To investigate the cellular mechanisms underlying LMNA-related DCM using patient-derived iPSC-CMs.
  • To identify potential therapeutic targets for LMNA-related DCM.

Main Methods:

  • Generation of iPSC-CMs from patients with LMNA mutations.
  • Electrophysiological studies to assess cardiac function at the single-cell level.
  • Analysis of signaling pathways, including platelet-derived growth factor (PDGF), in iPSC-CMs.

Main Results:

  • Mutant iPSC-CMs exhibited aberrant calcium homeostasis, leading to single-cell arrhythmias.
  • The platelet-derived growth factor (PDGF) signaling pathway was activated in iPSC-CMs with LMNA mutations.
  • Inhibition of the PDGF pathway ameliorated the arrhythmic phenotypes in vitro.

Conclusions:

  • Aberrant PDGF pathway activation contributes to the pathogenesis of LMNA-related DCM.
  • PDGF receptor-β (PDGFRB) represents a potential therapeutic target for LMNA-related DCM.

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