[GATA4/MYOM2 axis mediates the protective effect of folic acid on sodium arsenite-exposed cardiomyocytes and mouse embryonic heart development].

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. 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. 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. 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.