BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis
BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis
复制标题
非综合征法洛四联症中 BVES 下调与心室流出道狭窄相关。
DOI：
10.1038/s41598-020-70806-4
复制
发表时间：
2020-08-25
影响因子：
4.6
通讯作者：
Yuan，Wuzhou
中科院分区：
文献类型：
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作者：
Shi，Yan;Li，Yongqing;Yuan，Wuzhou
BVES是一种跨膜蛋白，我们的前期工作证明法洛四联症（tetralogy of fallot，TOF）患者BVES基因的单核苷酸突变可导致BVES转录下调。然而，BVES与TOF发病机制之间的关系尚未确定。本文报道了我们对BVES与右室流出道狭窄关系的研究结果，与对照组相比，大多数TOF标本中BVES表达显著下调。第二心脏区域（SHF）调控网络基因NKX2. 5、GATA 4和HAND2的表达在TOF样本中也降低。在斑马鱼中，bvesmRNA的敲除导致成环缺陷和心室流出道（VOT）狭窄，这主要是通过注射bvesmRNA来挽救的。在斑马鱼中，bvesmRNA的敲除也降低了SHF基因的表达，如nkx2.5，gata4和hand2，与TOF样品的结果一致。双荧光报告系统分析表明，BVES正调控GATA 4、NKX2. 5和HAND2启动子的转录活性。在斑马鱼中，nkx2.5mRNA部分地挽救了bvesknockdown引起的VOT狭窄。这些结果提示BVES表达下调可能与非综合征型TOF的RVOT狭窄有关，BVES可能参与了斑马鱼VOT的发生发展。
BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations ofBVESin tetralogy of fallot (TOF) patients cause a downregulation ofBVEStranscription. However, the relationship betweenBVESand the pathogenesis of TOF has not been determined. Here we reported our research results about the relationship betweenBVESand the right ventricular outflow tract (RVOT) stenosis.BVESexpression was significantly downregulated in most TOF samples compared with controls. The expression of the second heart field (SHF) regulatory network genes, includingNKX2.5,GATA4andHAND2, was also decreased in the TOF samples. In zebrafish,bvesknockdown resulted in looping defects and ventricular outflow tract (VOT) stenosis, which was mostly rescued by injectingbvesmRNA.bvesknockdown in zebrafish also decreased the expression of SHF genes, such asnkx2.5,gata4andhand2, consistent with the TOF samples` results. The dual-fluorescence reporter system analysis showed thatBVESpositively regulated the transcriptional activity ofGATA4,NKX2.5andHAND2promoters. In zebrafish,nkx2.5mRNA partially rescued VOT stenosis caused bybvesknockdown. These results indicate thatBVESdownregulation may be associated with RVOT stenosis of non-syndromic TOF, andbvesis probably involved in the development of VOT in zebrafish.