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. Former studies determined that miR-155 is elevated in GDM patients. In the present study, we explored the potential role of miR-155 on high glucose-induced cardiac developmental defects. Methods: Serum miR-155 of GDM patients was determined by using ELISA. Fetal cardiac characteristics were collected by echocardiography. Zebrafish embryos were exposed to 2% D-Glucose in a fluctuating manner. The expression levels of miR-155, Ets1 and cardiac specific genes were evaluated by real-time PCR or western blot. Reactive oxygen species (ROS) were detected by DCFH-DA. Findings: High glucose exposure in zebrafish embryos altered the morphology of the heart, increased the expression of miR-155 and 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. Knockdown of miR-155 could rescue high glucose-induced zebrafish heart developmental defects. Besides, miR-155 levels are increased in serum from GDM patients and are correlated with fetal cardiac structural changes. Moreover, loss of miR-155 blocked Igf1 survival pathway and induced apoptosis and may thus cause zebrafish cardiac developmental defects. Interpretation: 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. Funding：This work was supported by grants from: (1) the Youth Program of National Natural Science Foundation (NSF)of China (81200125) to LY; (2) the Priority Academic Program Development (PAPD) and the Key Project of Natural Science Foundation of the Higher Education Institutions (17KJA310001) to LY; (3) the Six Talent Peaks Project (STPP) of Jiangsu Province (2015-WSN-032) to ZXT. Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics Approval Statement: The studies involving human participants were reviewed and approved by Ethical Committee, Jiangsu province Hospital. The patients/participants provided their written informed consent to participate in this study. Zebrafish maintenance and procedures were conducted in accordance with the medical ethics committee of Nanjing Medical University. All experiments were approved by the medical ethics committee of Nanjing Medical University.