EPAS1 induction drives myocardial degeneration in desmoplakin-cardiomyopathy.

ABSTRACT: Arrhythmogenic cardiomyopathy (ACM) is frequently attributed to desmosomal mutations, such as those in the desmoplakin (DSP) gene. Patients with DSP-cardiomyopathy are predisposed to myocardial degeneration and arrhythmias. Despite advancements, the underlying molecular mechanisms remain incompletely understood, thus limiting therapeutic options. Here, we employed spatial transcriptomics on an explanted heart from a patient with a pathogenic DSP variant. Our transcriptional analysis revealed endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. Elevated EPAS1 levels were associated with mitochondrial dysfunction and hypoxic stress in both human-relevant in vitro ACM models and additional ex

SUBMITTER: Kyriakopoulou E 

PROVIDER: S-EPMC11872638 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature