BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis

• Published in: Scientific reports Vol. 10; no. 1; p. 14167
• Main Authors: Shi, Yan, Li, Yongqing, Wang, Yuequn, Zhu, Ping, Chen, Yu, Wang, Heng, Yue, Shusheng, Xia, Xiaohui, Chen, Jimei, Jiang, Zhigang, Zhou, Chengbin, Cai, Wanwan, Yuan, Haiyun, Wu, Yueheng, Wan, Yongqi, Li, Xiaohong, Zhu, Xiaolan, Zhou, Zuoqiong, Dai, Guo, Li, Fang, Mo, Xiaoyang, Ye, Xiangli, Fan, Xiongwei, Zhuang, Jian, Wu, Xiushan, Yuan, Wuzhou
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.08.2020; Nature Publishing Group
• Subjects: 631/136/1425; 631/136/1455; Abnormalities, Multiple; Animals; Biology; Cardiovascular disease; Cell Adhesion Molecules - biosynthesis; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - physiology; Child; Child, Preschool; Congenital diseases; Coronary Vessel Anomalies; Coronary vessels; Danio rerio; Defects; Disease Models, Animal; Down-Regulation; Embryos; Ethics; Female; Foramen Ovale, Patent; Gene Expression Regulation; Genes; Heart; Heart - embryology; Homeobox Protein Nkx-2.5 - genetics; Homeobox Protein Nkx-2.5 - physiology; Humanities and Social Sciences; Humans; Infant; Male; Middle Aged; multidisciplinary; Muscle Proteins - biosynthesis; Muscle Proteins - genetics; Muscle Proteins - physiology; Mutation; Nkx2.5 protein; Proteins; Pulmonary arteries; RNA, Messenger - genetics; Science; Science (multidisciplinary); Stenosis; Tetralogy of Fallot; Tetralogy of Fallot - complications; Tetralogy of Fallot - genetics; Tetralogy of Fallot - metabolism; Tetralogy of Fallot - pathology; Transcription; Veins & arteries; Ventricle; Ventricular Outflow Obstruction - embryology; Ventricular Outflow Obstruction - etiology; Ventricular Outflow Obstruction - genetics; Zebrafish; Zebrafish - embryology; Zebrafish Proteins - genetics; Zebrafish Proteins - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-70806-4

BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations of BVES in tetralogy of fallot (TOF) patients cause a downregulation of BVES transcription. However, the relationship between BVES and the pathogenesis of TOF has not been determined. Here we reported our research results about the relationship between BVES and the right ventricular outflow tract (RVOT) stenosis. BVES expression was significantly downregulated in most TOF samples compared with controls. The expression of the second heart field (SHF) regulatory network genes, including NKX2.5 , GATA4 and HAND2 , was also decreased in the TOF samples. In zebrafish, bves knockdown resulted in looping defects and ventricular outflow tract (VOT) stenosis, which was mostly rescued by injecting bves mRNA. bves knockdown in zebrafish also decreased the expression of SHF genes, such as nkx2.5 , gata4 and hand2 , consistent with the TOF samples` results. The dual-fluorescence reporter system analysis showed that BVES positively regulated the transcriptional activity of GATA4 , NKX2.5 and HAND2 promoters. In zebrafish, nkx2.5 mRNA partially rescued VOT stenosis caused by bves knockdown. These results indicate that BVES downregulation may be associated with RVOT stenosis of non-syndromic TOF, and bves is probably involved in the development of VOT in zebrafish.