Odelin Gaëlle, Faure Emilie, Maurel-Zaffran Corinne, Zaffran Stéphane
Aix Marseille University, INSERM, Marseille Medical Genetics, U1251, 13005 Marseille, France.
Aix Marseille University, CNRS UMR7288, IBDM, 13009 Marseille, France.
J Cardiovasc Dev Dis. 2019 Nov 2;6(4):39. doi: 10.3390/jcdd6040039.
Among the aortic valve diseases, the bicuspid aortic valve (BAV) occurs when the aortic valve has two leaflets (cusps), rather than three, and represents the most common form of congenital cardiac malformation, affecting 1-2% of the population. Despite recent advances, the etiology of BAV is poorly understood. We have recently shown that is expressed in endothelial and cardiac neural crest derivatives that normally contribute to aortic valve development and that lack of in these cells leads to aortic valve defects including partially penetrant BAV formation. Dysregulated expression of endothelial nitric oxide synthase (Nos3) is associated with BAV. To investigate the relationship between and during aortic valve development, we performed inter-genetic cross. While single heterozygous mice had normal valve formation, the compound ; mice had BAV malformations displaying an in vivo genetic interaction between these genes for normal valve morphogenesis. Moreover, in vivo and in vitro experiments demonstrate that Krox20 directly binds to proximal promoter to activate its expression. Our data suggests that Krox20 is a regulator of nitric oxide in endothelial-derived cells in the development of the aortic valve and concludes on the interaction of and in BAV formation.
在主动脉瓣疾病中，二叶式主动脉瓣（BAV）是指主动脉瓣有两个瓣叶（瓣尖）而非三个瓣叶，它是先天性心脏畸形最常见的形式，影响着1%至2%的人群。尽管最近有了进展，但BAV的病因仍知之甚少。我们最近发现，[此处原文缺失具体基因名称]在通常对主动脉瓣发育有贡献的内皮细胞和心脏神经嵴衍生物中表达，并且这些细胞中缺乏[此处原文缺失具体基因名称]会导致主动脉瓣缺陷，包括部分穿透性BAV的形成。内皮型一氧化氮合酶（Nos3）表达失调与BAV有关。为了研究主动脉瓣发育过程中[此处原文缺失具体基因名称]与[此处原文缺失具体基因名称]之间的关系，我们进行了基因间杂交。虽然单杂合小鼠瓣膜形成正常，但复合杂合子[此处原文缺失具体基因名称]小鼠有BAV畸形，显示出这些基因之间在正常瓣膜形态发生方面存在体内遗传相互作用。此外，体内和体外实验表明，Krox20直接结合到[此处原文缺失具体基因名称]近端启动子以激活其表达。我们的数据表明，Krox20是主动脉瓣发育过程中内皮衍生细胞中一氧化氮的调节因子，并得出了[此处原文缺失具体基因名称]与[此处原文缺失具体基因名称]在BAV形成中的相互作用的结论。
