BACKGROUND Tetralogy of Fallot (TF) is a severe congenital defect of heart development. Fine-tuned sequential activation of Notch signaling genes is responsible for proper heart chamber development. Mutations in Notch genes have been associated with TF. The aim of this study was to analyze the activity of the Notch pathway in cardiac mesenchymal cells derived from ventricular tissue of TF patients. METHODS Cardiac mesenchymal cells were isolated from 42 TF patients and from 14 patients with ventricular septal defects (VSDs), used as a comparison group. The Notch pathway was analyzed by estimating the expression of Notch-related genes by qPCR. Differentiation and proliferation capacity of the cells was estimated. RESULTS The TF-derived cells demonstrated a dysregulated pattern of Notch-related gene expression comparing to VSD-derived cells. Correlation of Notch signaling activation level by HEY1 / HES1 expression level with proliferation and cardiogenic-like differentiation of cardiac mesenchymal cells was observed but not with clinical parameters nor with the age of the patients. CONCLUSIONS The data suggest a contribution of dysregulated Notch signaling to the pathogenesis of tetralogy of Fallot and importance of Notch signaling level for the functional state of cardiac mesenchymal cells, which could be critical considering these cells for potential cell therapy approaches.

中文翻译：

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法洛四联症患者心脏间充质细胞中Notch信号的失调

背景法洛四联症（TF）是一种严重的先天性心脏发育缺陷。Notch 信号基因的微调顺序激活负责适当的心室发育。Notch 基因的突变与 TF 相关。本研究的目的是分析来自 TF 患者心室组织的心脏间充质细胞中 Notch 通路的活性。方法从42例TF患者和14例室间隔缺损(VSDs)患者中分离出心脏间充质细胞，作为对照组。通过 qPCR 估计 Notch 相关基因的表达来分析 Notch 通路。估计细胞的分化和增殖能力。结果 与 VSD 衍生细胞相比，TF 衍生细胞表现出 Notch 相关基因表达的失调模式。观察到通过 HEY1/HES1 表达水平的 Notch 信号激活水平与心脏间充质细胞的增殖和心源性样分化的相关性，但与临床参数和患者年龄无关。结论 数据表明，Notch 信号失调对法洛四联症发病机制的贡献以及 Notch 信号水平对心脏间充质细胞功能状态的重要性，考虑到这些细胞用于潜在的细胞治疗方法，这可能是至关重要的。