[GATA4/MYOM2轴介导叶酸对亚砷酸钠暴露心肌细胞和小鼠胚胎心脏发育的保护作用]。

Lingzi Zhuang, Mengying Gao, Lingli Wang, Yuxin Feng, Xiaoyan Pan, Xiaohong Wang
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引用次数: 0

摘要

目的:通过生物信息学分析和体内外实验,探讨叶酸在亚砷酸钠诱导大鼠胚胎心脏畸形及心肌细胞分化成熟过程中调节GATA4/MYOM2轴的作用。方法:采用R语言筛选野生型和GATA4-G296S突变组在GSE85623中hiPSC向心肌细胞分化不同时间点的差异表达基因,探讨关键基因的生物学功能。采用动物实验观察75 mg/L亚砷酸钠和10.6 mg/kg叶酸对胎鼠心脏发育的影响,并采用免疫组化方法检测胎鼠心肌组织中GATA4和MYOM2的表达。采用Western blot和实时荧光定量PCR检测叶酸和亚砷酸钠对hiPSC细胞中GATA4和MYOM2 mRNA和蛋白表达的影响。构建GATA4稳定过表达的hiPSC细胞系,然后用亚砷酸钠处理GATA4过表达组和对照组,用Western blot检测MYOM2蛋白的表达。结果:京都基因与基因组百科全书(KEGG)分析显示,PI3K-Akt信号通路、ECM受体相互作用通路和扩张型心肌病相关基因富集差异基因。基因本体(GO)分析表明,差异基因富集于整合素结合、细胞外基质结构组分、肌动蛋白结合等生物过程中,与细胞外结构组织、细胞外基质组织、肌肉收缩、肌肉组织发育等分子功能相关,主要富集于突触膜、肌组等细胞组分。亚砷酸钠暴露组胎儿心脏畸形发生率显著高于对照组和叶酸治疗组,心肌组织中GATA4和MYOM2蛋白表达显著低于对照组和叶酸治疗组(P<0.05)。亚砷酸钠处理后,与对照组相比,hiPSC细胞中GATA4和MYOM2 mRNA和蛋白表达水平显著降低,叶酸处理后可恢复表达水平,且随着叶酸浓度的增加,其表达水平逐渐升高,组间差异有统计学意义(P<0.05)。过表达GATA4可逆转亚砷酸钠引起的MYOM2低表达。结论:GATA4通过调节MYOM2的表达,在亚砷酸钠暴露大鼠心脏畸形的发生及心肌细胞分化成熟过程中起关键作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
[GATA4/MYOM2 axis mediates the protective effect of folic acid on sodium arsenite-exposed cardiomyocytes and mouse embryonic heart development].

Objective: To explore the role of folic acid in regulating GATA4/MYOM2 axis in sodium arsenite-induced rat embryonic heart malformation and cardiomyocyte differentiation and maturation by bioinformatics analysis and in vivo and in vitro experiments.

Methods: R language was used to screen differentially expressed genes between wild type and GATA4-G296S mutant groups at different time points of hiPSC differentiation into cardiomyocytes in GSE85623, and explore the biological functions of key genes. Animal experiments were performed to observe the effects of 75 mg/L sodium arsenite and 10.6 mg/kg folic acid on fetal rat heart development, and the expression of GATA4 and MYOM2 in fetal rat myocardium was evaluated by immunohistochemistry. Western blot and real-time fluorescence quantitative PCR were used to detect the effects of folic acid and sodium arsenite on the mRNA and protein expression of GATA4 and MYOM2 in hiPSC cells. A GATA4 stable overexpression hiPSC cell line was constructed, then the GATA4 overexpression group and the control group were treated with sodium arsenite, and the protein expression of MYOM2 was detected by Western blot.

Results: Kyoto encyclopedia of genes and genomes(KEGG)analysis showed that differential genes were enriched in PI3K-Akt signaling pathway, ECM receptor interaction pathway, and genes related to dilated cardiomyopathy. Gene ontology(GO)analysis showed that differential genes were enriched in biological processes such as integrin binding, extracellular matrix structural components, and actin binding, and were related to molecular functions such as extracellular structure organization, extracellular matrix organization, muscle contraction, and muscle tissue development, and were mainly enriched in cell components such as synaptic membrane and myotome. The incidence of fetal cardiac malformation in the sodium arsenite exposure group was significantly higher than that in the control group and the folic acid treatment group, and the protein expression of GATA4 and MYOM2 in the myocardial tissue was significantly lower than that in the control group and the folic acid treatment group(P<0.05). After sodium arsenite treatment, the mRNA and protein expression levels of GATA4 and MYOM2 in hiPSC cells were significantly reduced compared with the control group, and their expression levels could be restored after folate treatment, and with the increase of folate concentration, their expression levels gradually increased, with statistically significant differences between groups(P<0.05). Overexpression of GATA4 can reverse the low expression of MYOM2 caused by sodium arsenite.

Conclusion: GATA4 plays a key role in the development of cardiac malformation in rats exposed to sodium arsenite and differentiation and maturation of cardiomyocytes by regulating the expression of MYOM2.

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