Center for Cardiovascular Research and.
The Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA.
JCI Insight. 2017 Nov 2;2(21):91353. doi: 10.1172/jci.insight.91353.
An ascending aortic aneurysm (AscAA) is a life-threatening disease whose molecular basis is poorly understood. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV), which is associated with AscAA. Here, we describe a potentially novel role for Notch1 in AscAA. We found that Notch1 haploinsufficiency exacerbated the aneurysmal aortic root dilation seen in the Marfan syndrome mouse model and that heterozygous deletion of Notch1 in the second heart field (SHF) lineage recapitulated this exacerbated phenotype. Additionally, Notch1+/- mice in a predominantly 129S6 background develop aortic root dilation, indicating that loss of Notch1 is sufficient to cause AscAA. RNA sequencing analysis of the Notch1.129S6+/- aortic root demonstrated gene expression changes consistent with AscAA. These findings are the first to our knowledge to demonstrate an SHF lineage-specific role for Notch1 in AscAA and suggest that genes linked to the development of BAV may also contribute to the associated aortopathy.
升主动脉瘤（AscAA）是一种危及生命的疾病，其分子基础尚未完全阐明。NOTCH1 突变与二叶式主动脉瓣（BAV）有关，而 BAV 与 AscAA 相关。在这里，我们描述了 Notch1 在 AscAA 中的一个潜在的新作用。我们发现 Notch1 杂合不足加剧了马凡综合征小鼠模型中所见的升主动脉根部扩张，而第二心脏场（SHF）谱系中的 Notch1 杂合缺失再现了这种加剧的表型。此外，在主要为 129S6 背景的 Notch1+/- 小鼠中，主动脉根部扩张，表明 Notch1 的缺失足以导致 AscAA。对 Notch1.129S6+/- 主动脉根部的 RNA 测序分析表明，基因表达的变化与 AscAA 一致。这些发现是我们所知的首次证明 Notch1 在 AscAA 中具有 SHF 谱系特异性作用，并表明与 BAV 发育相关的基因也可能导致相关的主动脉病变。
