Abstract：
A better understanding of the underlying pathomechanisms of diastolic dysfunction is crucial for the development of targeted therapeutic options with the aim to increase the patients\' quality of life. In order to shed light on the processes involved, suitable models are required. Here, effects of endothelin-1 (ET-1) treatment on cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) were investigated. While it is well established, that ET-1 treatment induces hypertrophy in cardiomyocytes, resulting changes in cell mechanics and contractile behavior with focus on relaxation have not been examined before. Cardiomyocytes were treated with 10 nM of ET-1 for 24 h and 48 h, respectively. Hypertrophy was confirmed by real-time deformability cytometry (RT-DC) which was also used to assess the mechanical properties of cardiomyocytes. For investigation of the contractile behavior, 24 h phase contrast video microscopy was applied. To get a deeper insight into changes on the molecular biological level, gene expression analysis was performed using the NanoString nCounter® cardiovascular disease panel. Besides an increased cell size, ET-1 treated cardiomyocytes are stiffer and show an impaired relaxation. Gene expression patterns in ET-1 treated hiPSC derived cardiomyocytes showed that pathways associated with cardiovascular diseases, cardiac hypertrophy and extracellular matrix were upregulated while those associated with fatty acid metabolism were downregulated. We conclude that alterations in cardiomyocytes after ET-1 treatment go far beyond hypertrophy and represent a useful model for diastolic dysfunction.
摘要：
更好地了解舒张功能不全的潜在病理机制对于开发旨在提高患者生活质量的靶向治疗方案至关重要。为了阐明所涉及的过程，需要合适的模型。这里,研究了内皮素-1（ET-1）处理对人诱导多能干细胞（hiPSCs）来源的心肌细胞的影响。虽然它已经确立，ET-1治疗诱导心肌细胞肥大，以前没有检查过专注于放松的细胞力学和收缩行为的变化。心肌细胞用10nMET-1处理24小时和48小时，分别。通过实时可变形性细胞术（RT-DC）证实肥大，该细胞也用于评估心肌细胞的机械性能。为了调查收缩行为，应用24h相衬视频显微镜。为了更深入地了解分子生物学水平的变化，使用NanoStringnCounter®心血管疾病小组进行基因表达分析。除了增加细胞大小，ET-1处理的心肌细胞更硬并显示受损的松弛。ET-1处理的hiPSC衍生心肌细胞的基因表达模式显示与心血管疾病相关的通路,心脏肥大和细胞外基质上调，而与脂肪酸代谢相关的则下调。我们得出的结论是，ET-1治疗后心肌细胞的变化远远超出了肥大，代表了舒张功能障碍的有用模型。
