EphA4 is highly expressed in the atria of heart and its deletion leads to atrial hypertrophy and electrocardiographic abnormalities in rats
EphA4 is highly expressed in the atria of heart and its deletion leads to atrial hypertrophy and electrocardiographic abnormalities in rats
复制标题
DOI：
10.1016/j.lfs.2021.119595
复制
发表时间：
2021-05-11
期刊：
影响因子：
6.1
通讯作者：
Zhang, Lianfeng
中科院分区：
文献类型：
--
作者：
Li, Jingwen;Dong, Wei;Zhang, Lianfeng
目的：EphA4是Eph受体家族成员，主要表达于中枢神经系统（CNS），参与中枢神经系统发育和多种疾病。由于EphA4表达的变异性，我们想知道EphA4是否在其他组织中也有表达，EphA4在其中起什么作用？材料和方法：我们构建了EphA4基因敲除（KO）大鼠系，其红色荧光标记蛋白由插入EphA4启动子下游的mCherry盒编码作为报告基因。使用该系统，我们观察到EphA4在心房和大脑中的高表达。关键发现：EphaA4 KO大鼠（EphA4-/-）在6月龄时出现明显的心房肥厚，房心重量比和心房心肌细胞横截面积增加。EphA4- /-降低了大鼠心房舒张末期容积（EDV）、心房射血分数（EF）和左室EF。他们还表现出QRS复合物的振幅和QT间期增加，p波不可见。RNA测序结果显示，EphA4 KO改变了多个参与转录翻译、离子结合、代谢和细胞粘附调控的基因的转录。EphA4的缺失降低了参与心脏重构的IGF1 mRNA和蛋白的表达。意义：我们的数据表明EphA4在心房中高表达，其缺失导致心房功能障碍。我们的发现也提示EphA4 KO大鼠可能是研究心房重构的潜在模型。
Aims: EphA4 is a member of the Eph receptor family, and expressed mainly in central nervous system (CNS), which is involved in CNS development and multiple diseases. Due to the variability in EphA4 expression, we wondered if EphA4 is expressed in other tissues, and what role does EphA4 play?Materials and methods: We generated an EphA4 knockout (KO) rat line with red fluorescent marker protein encoded by the mCherry cassette inserted downstream of the EphA4 promoter as a reporter. Using this system, we observed high expression of EphA4 in the heart atria and in the brain.Key findings: EphaA4 KO rats (EphA4-/- ) developed obvious atrial hypertrophy with an increased atria-to-heart weight ratio and atrial cardiomyocyte cross-sectional area at six months of age. EphA4- /- rats had reduced atrial end diastolic volume (EDV), atrial ejection fraction (EF) and left ventricular EF. They also exhibited increased amplitude of QRS complexes and QT intervals, with invisible p waves. RNA sequencing revealed that EphA4 KO altered the transcription of multiple genes involved in regulation of transcription and translation, ion binding, metabolism and cell adhesion. Deletion of EphA4 reduced IGF1 mRNA and protein expression, which is involved in cardiac remodeling.Significance: Our data demonstrated that EphA4 was highly expressed in the atria and its deletion caused atrial dysfunction. Our findings also suggested that the EphA4 KO rat could be a potential model for studies on atrial remodeling.