NADPH oxidases (NOX) are a major source of reactive oxygen species (ROS) production in the heart. ROS signaling regulates gene expression, cell proliferation, apoptosis, and migration. However, the role of NOX2 in embryonic heart development remains elusive. We hypothesized that deficiency of Nox2 disrupts endocardial to mesenchymal transition (EndMT) and results in congenital septal and valvular defects. Our data show that 34% of Nox2^-/- neonatal mice had various congenital heart defects (CHDs) including atrial septal defects (ASD), ventricular septal defects (VSD), atrioventricular canal defects (AVCD), and malformation of atrioventricular and aortic valves. Notably, Nox2^-/- embryonic hearts show abnormal development of the endocardial cushion as evidenced by decreased cell proliferation and an increased rate of apoptosis. Additionally, Nox2 deficiency disrupted EndMT of atrioventricular cushion explants ex vivo. Furthermore, treatment with N-acetylcysteine (NAC) to reduce ROS levels in the wild-type endocardial cushion explants decreased the number of cells undergoing EndMT. Importantly, deficiency of Nox2 was associated with reduced expression of Gata4, Tgfβ2, Bmp2, Bmp4, and Snail1, which are critical to endocardial cushion and valvoseptal development. We conclude that NOX2 is critical to EndMT, endocardial cushion cell proliferation, and normal embryonic heart development.

中文翻译：

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NOX2对心内膜向间质过渡和心脏发育至关重要。

NADPH氧化酶（NOX）是心脏中活性氧（ROS）产生的主要来源。ROS信号传导调节基因表达，细胞增殖，凋亡和迁移。但是，NOX2在胚胎心脏发育中的作用仍然难以捉摸。我们假设Nox2的缺乏会破坏心内膜向间质的过渡（EndMT），并导致先天性中隔和瓣膜缺损。我们的数据显示34％的Nox2 ^-/-新生小鼠患有各种先天性心脏缺陷（CHD），包括房间隔缺损（ASD），室间隔缺损（VSD），房室管缺损（AVCD）以及房室和主动脉瓣畸形。值得注意的是，Nox2 ^-/-胚胎心脏显示出心内膜垫的异常发育，如细胞增殖减少和凋亡率增加所证明。此外，Nox2缺乏症离体破坏了房室垫外植体的EndMT 。此外，用N-乙酰半胱氨酸（NAC）进行处理以降低野生型心内膜垫层外植体中ROS的水平，可以减少进行EndMT的细胞数量。重要的是，缺乏NOX2用减少的表达相关GATA4，TGFβ2，BMP2，的Bmp4，和SNAIL1，这对心内膜垫和瓣膜的发育至关重要。我们得出结论，NOX2对于EndMT，心内膜垫细胞增殖和正常胚胎心脏发育至关重要。