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EPAS1 induction drives myocardial degeneration in desmoplakin-cardiomyopathy

Eirini Kyriakopoulou1, Sebastiaan J van Kampen1, Martijn Wehrens1

  • 1Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands.

Iscience
|March 4, 2025
PubMed

Insights

Pathogenic desmoplakin (DSP) variants cause arrhythmogenic cardiomyopathy (ACM) by disrupting mitochondrial function. Increased endothelial PAS domain-containing protein 1 (EPAS1) levels are linked to this degeneration, suggesting EPAS1 as a therapeutic target in DSP-cardiomyopathy.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Arrhythmogenic cardiomyopathy (ACM) is often caused by desmoplakin (DSP) gene mutations.
  • DSP-cardiomyopathy leads to myocardial degeneration and arrhythmias, but mechanisms are unclear.
  • Understanding these mechanisms is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying DSP-cardiomyopathy.
  • To identify key regulators of myocardial degeneration in DSP-cardiomyopathy.
  • To explore potential therapeutic targets for this condition.

Main Methods:

  • Spatial transcriptomics was performed on an explanted heart from a patient with a pathogenic DSP variant.
  • In vitro ACM models and additional explanted hearts were analyzed.
  • Transcriptional and mitochondrial function analyses were conducted.

Main Results:

  • Endothelial PAS domain-containing protein 1 (EPAS1) was identified as a potential regulator of mitochondrial homeostasis.
  • Elevated EPAS1 levels correlated with mitochondrial dysfunction and hypoxic stress in DSP-cardiomyopathy.
  • DSP-cardiomyopathy cardiomyocytes showed mitochondrial dysfunction, apoptosis, and impaired contractility linked to increased EPAS1.

Conclusions:

  • EPAS1 is implicated as a key regulator of myocardial degeneration in DSP-cardiomyopathy.
  • These findings may extend to other forms of arrhythmogenic cardiomyopathy.
  • EPAS1 represents a potential therapeutic target for DSP-cardiomyopathy and related conditions.

Keywords:
Cardiovascular medicineCell biologyTranscriptomics

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