Kyriakopoulou Eirini, van Kampen Sebastiaan J, Wehrens Martijn, Han Su Ji, de Ruiter Hesther, Monshouwer-Kloots Jantine, Marshall Emma, Brodehl Andreas, van der Kraak Petra, Te Riele Anneline S J M, van Aarnhem Egidius E H L, van Laake Linda W, Tsui Hoyee, Boogerd Cornelis J, van Rooij Eva
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands.
Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Bad Oeynhausen, Germany.
iScience. 2025 Jan 25;28(3):111895. doi: 10.1016/j.isci.2025.111895. eCollection 2025 Mar 21.
Arrhythmogenic cardiomyopathy (ACM) is frequently attributed to desmosomal mutations, such as those in the desmoplakin () 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 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 ACM models and additional explanted hearts with genetic cardiomyopathy. Collectively, cardiomyocytes bearing pathogenic variants exhibit mitochondrial dysfunction, increased apoptosis, and impaired contractility, which are linked to the increased EPAS1 levels. These findings implicate EPAS1 as a key regulator of myocardial degeneration in DSP-cardiomyopathy, which expand to other forms of ACM.
致心律失常性心肌病（ACM）通常归因于桥粒突变，例如桥粒斑蛋白（DSP）基因中的突变。患有DSP心肌病的患者易发生心肌变性和心律失常。尽管取得了进展，但其潜在的分子机制仍未完全了解，从而限制了治疗选择。在此，我们对一名患有致病性变异的患者的离体心脏进行了空间转录组学研究。我们的转录分析表明，含内皮 PAS 结构域蛋白 1（EPAS1）是应激心肌细胞中线粒体稳态的潜在调节因子。在与人类相关的 ACM 模型以及其他患有遗传性心肌病的离体心脏中，EPAS1 水平升高与线粒体功能障碍和缺氧应激相关。总体而言，携带致病性变异的心肌细胞表现出线粒体功能障碍、凋亡增加和收缩力受损，这些都与EPAS1水平升高有关。这些发现表明，EPAS1是DSP心肌病中心肌变性的关键调节因子，这一结论可扩展到其他形式的ACM。
