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EPAS1 directs a network of genes implicated in mitochondrial dysfunction in arrhythmogenic cardiomyopathy [Spatial Transcriptomics]

ABSTRACT: Patients diagnosed with arrhythmogenic cardiomyopathy (ACM) often harbor desmosomal mutations, predisposing them to arrhythmia and sudden cardiac death. The molecular mechanisms underlying pathobiology remain incompletely understood, which is reflected by the limited number of therapeutic strategies. Here, we performed spatially resolved transcriptomics on an explanted heart isolated from a patient bearing a mutation in desmoplakin. Exploration of the transcriptional atlas uncovered endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. By combining these data with multiple models of cardiac disease, we show that induced EPAS1 levels activate expression of genes involved in mitophagy and the antioxidant response. Findings were validated in additional explanted heart from ACM and dilated cardiomyopathy patients. Together, genetically impaired cardiomyocytes display mitochondrial dysfunction, consequently resulting in stabilization of EPAS1. In turn, this factor dictates a gene network involved in mitigating the adverse effects of oxidative stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213540 | GEO | 2025/09/14

REPOSITORIES: GEO

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EPAS1 directs a network of genes implicated in mitochondrial dysfunction in arrhythmogenic cardiomyopathy [RNA-seq]

Project description:Patients diagnosed with arrhythmogenic cardiomyopathy (ACM) often harbor desmosomal mutations, predisposing them to arrhythmia and sudden cardiac death. The molecular mechanisms underlying pathobiology remain incompletely understood, which is reflected by the limited number of therapeutic strategies. Here, we performed spatially resolved transcriptomics on an explanted heart isolated from a patient bearing a mutation in desmoplakin. Exploration of the transcriptional atlas uncovered endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. By combining these data with multiple models of cardiac disease, we show that induced EPAS1 levels activate expression of genes involved in mitophagy and the antioxidant response. Findings were validated in additional explanted heart from ACM and dilated cardiomyopathy patients. Together, genetically impaired cardiomyocytes display mitochondrial dysfunction, consequently resulting in stabilization of EPAS1. In turn, this factor dictates a gene network involved in mitigating the adverse effects of oxidative stress.

2025-09-14 | GSE213539 | GEO

EPAS1 induction drives myocardial degeneration in Desmoplakin-cardiomyopathy [TOMO-seq]

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EPAS1 induction drives myocardial degeneration in Desmoplakin-cardiomyopathy [RNA-seq]

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Project description:Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiomyopathy. The pathophysiological events are well understood, yet the underlying molecular mechanisms remain undefined. Here, we created a novel research platform comprising of patient originated hiPSC-derived cardiomyocytes bearing a pathological PKP2 mutation (PKP2 c.2013delC/WT), a novel knock-in murine model carrying the equivalent mutation (Pkp2 c.1755delA/WT), and human explanted ACM hearts, to identify disease driving mechanisms. Pkp2 c.1755delA/WT mice displayed reduced desmosomal and adherens junctions protein levels and protein disarray of the intercalated discs in areas of active fibrotic remodeling. These findings were validated in hiPSC-derived cardiomyocytes and human explanted ACM hearts. Led by proteomics data, we demonstrated that the ubiquitin-proteasome system was responsible for the observed desmosomal protein degradation. The research platform presented here provides a strong scientific basis to identify bona fide pathological processes and will aid in the development of potential therapies for the prevention of ACM disease progression.

2023-11-18 | PXD020605 | Pride

Desmosomal protein degradation as underlying causes of arrhythmogenic cardiomyopathy [PKP2 c.1755delA/WT and WT]

Project description:Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiomyopathy. The pathophysiological events are well understood, yet the underlying molecular mechanisms remain undefined. Here we use patient originated hiPSC-derived cardiomyocytes bearing a pathogenic PKP2 mutation (PKP2 c.2013delC/WT), a corresponding knock-in mouse model carrying the equivalent murine mutation (Pkp2 c.1755delA/WT), and human explanted ACM hearts, to identify disease driving mechanisms. Pkp2 c.1755delA/WT mice over time displayed signs of ACM as observed by cardiac dysfunction and pathological remodeling. At a molecular level these mice showed a reduction in desmosomal and adherens junction proteins as well as disarray of the intercalated discs in areas of active fibrotic remodeling. These findings were validated in the mutant hiPSC-derived cardiomyocytes as well as human explanted ACM hearts, indicating both the conservation and relevance of protein degradation in the pathogenesis of the disease. Led by proteomics data, we demonstrated that the ubiquitin-proteasome system was responsible for the observed desmosomal protein degradation. These findings show the importance of appropriate disease modeling and provide means for therapeutic intervention for the prevention of ACM disease progression.

2023-03-23 | GSE199925 | GEO

Desmosomal protein degradation as underlying causes of arrhythmogenic cardiomyopathy

Project description:Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiomyopathy. The pathophysiological events are well understood, yet the underlying molecular mechanisms remain undefined. Here we use patient originated hiPSC-derived cardiomyocytes bearing a pathogenic PKP2 mutation (PKP2 c.2013delC/WT), a corresponding knock-in mouse model carrying the equivalent murine mutation (Pkp2 c.1755delA/WT), and human explanted ACM hearts, to identify disease driving mechanisms. Pkp2 c.1755delA/WT mice over time displayed signs of ACM as observed by cardiac dysfunction and pathological remodeling. At a molecular level these mice showed a reduction in desmosomal and adherens junction proteins as well as disarray of the intercalated discs in areas of active fibrotic remodeling. These findings were validated in the mutant hiPSC-derived cardiomyocytes as well as human explanted ACM hearts, indicating both the conservation and relevance of protein degradation in the pathogenesis of the disease. Led by proteomics data, we demonstrated that the ubiquitin-proteasome system was responsible for the observed desmosomal protein degradation. These findings show the importance of appropriate disease modeling and provide means for therapeutic intervention for the prevention of ACM disease progression.

2023-03-23 | GSE160289 | GEO

Exercise Reverses Dysregulated Gene Expression in a Desmoplakin Haplo-insufficient Mouse Model of Arrhythmogenic Cardiomyopathy

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EPAS1 induction drives myocardial degeneration in Desmoplakin-cardiomyopathy [RNA-seq]

Project description:EPAS1 induction drives myocardial degeneration in Desmoplakin-cardiomyopathy [RNA-seq]

| PRJNA1223854 | ENA

EPAS1 induction drives myocardial degeneration in Desmoplakin-cardiomyopathy [TOMO-seq]

Project description:EPAS1 induction drives myocardial degeneration in Desmoplakin-cardiomyopathy [TOMO-seq]

| PRJNA1223853 | ENA

Innate immune activation modulates contractile and electrical dysfunction in engineered heart tissue models fordesmoplakin(DSP)cardiomyopathy.

Project description:Desmosomes are specialized cell-cell junctions critically important in the heart, where their disruption promotes arrhythmogenic cardiomyopathy (ACM). Individuals carrying truncating variants in the desmosomal gene desmoplakin (DSP) often show a prominent inflammatory component in the absence of known antigenic stimuli, termed “hot phase” arrythmia. To assess the role of innate immune activation in DSP-cardiomyopathy, we generated engineered heart tissues (EHTs) from two patients with heterozygous DSP truncation variants (DSPtv, p.E1597X and p.R1951X). We also generated EHTs with homozygous DSP deletion (DSP-/-) for modeling. DSP-/- EHTs revealed impaired force production and reduced conduction velocity compared to isogenic controls, features consistent with ACM. RNA sequencing and protein characterization demonstrated a dramatic increase in innate immune activation in DSP-/- EHTs. Similarly, patient-derived DSPtv EHTs show enhanced sensitivity to inflammatory stimuli seen as reduced contractility and greater cytokine release. Inhibition of NFκB signaling improved baseline force production and mechanical response to strain in DSPtv EHTs, indicating that anti-inflammatory modulation may improve mechanical function in DSP deficient hearts. Furthermore, genomic correction of p.R1951X using adenine base editing reduced inflammatory biomarkers in cultured EHTs. Taken together, these data identify that DSPtv promote innate immune activation, creating an arrhythmogenic substrate in the concealed phase of ACM.

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