Effects of miR-155 on High Glucose Induced-Cardiac Developmental Defects of Zebrafish Embryos

Abstract Background: Gestational diabetes mellitus (GDM) is known to have a teratogenic effect on heart development. However, the underlying mechanisms are still unclear. Former studies determined that miR-155 is elevated in GDM patients. Besides, miR-155 is a key molecule for development. In the present study, we explored the potential role of miR-155 in heart development and the effect of miR-155 on high glucose-induced cardiac developmental defects.Methods: Zebrafish embryos were exposed to 2% D-Glucose in a fluctuating manner. Activators or inhibitors of miR-155, Ets1, and Igf1 were injected into one-cell stage embryos. The expression levels of miR-155, Ets1 and cardiac specific genes were evaluated by real-time PCR. The regulation of Igf1 by Ets1 was examined using luciferase assays. The levels of reactive oxygen species (ROS) were analyzed by DCFH-DA. Proteins involved in Igf1 pathway were detected by western blot analysis. Maternal serum miR-155 was determined using ELISA. Fetal cardiac structural and functional characteristics in diabetic or healthy pregnancies were performed by echocardiography.Results: miR-155 levels are increased in serum from GDM patients and are correlated with fetal cardiac structural changes. High glucose exposure in zebrafish embryos altered the morphology of the heart, impaired the heart function, and increased the expression of miR-155 as well as cardiac specific genes. Upregulation of miR-155 activated Igf1-Akt-Gsk3β pathway by targeting Ets1 and increased the production of ROS and may thereby exert teratogenic effect on cardiac development. In addition, knockdown of miR-155 blocked Igf1 survival pathway and induced apoptosis and may thus induced zebrafish cardiac developmental defects.Conclusion: miR-155 is a key molecule for heart development and is involved in high glucose-induced cardiac malformation, and it might be a novel biomarker as well as a potential drug target of high glucose-induced cardiac defects.