The Phosphorylation State of GSK3β Serine 9 Correlated to the Development of Valproic Acid-Associated Fetal Cardiac Teratogenicity, Fetal VPA Syndrome, Rescued by Folic Acid Administration

Yu, W.H., Ho, Y.L., Huang, P.T., Chu, S.L., Tsai, H.J., Liou, H.H.
Cardiovascular Toxicology   16(1): 34-45 (Journal)
Registered Authors
Tsai, Huai-Jen
Epithelial–mesenchymal transition (EMT), GSK3β, Heart valve, Teratogenicity, Valproic acid
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Anticonvulsants/toxicity*
  • Bradycardia/chemically induced
  • Bradycardia/congenital
  • Cell Proliferation
  • Dose-Response Relationship, Drug
  • Embryo, Nonmammalian
  • Female
  • Folic Acid/therapeutic use*
  • Glycogen Synthase Kinase 3/drug effects*
  • Glycogen Synthase Kinase 3/metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Heart Defects, Congenital/chemically induced*
  • Heart Defects, Congenital/prevention & control*
  • Heart Ventricles/abnormalities
  • Heart Ventricles/pathology
  • Male
  • Myocytes, Cardiac/drug effects
  • Phosphorylation
  • Serine/metabolism*
  • Valproic Acid/toxicity*
  • Vitamins/therapeutic use*
  • Zebrafish
25724324 Full text @ Cardiovasc. Toxicol.
The effects of the phosphorylation state of the glycogen synthase kinase 3β involved in the cardiac myocytes (jelly-like cells) epithelial-mesenchymal transition-associated migration during heart-valve formation were examined through the valproic acid-induced cardiac teratogenicity of transgenic line A34 of Tg in a the Brachydanio rerio embryo model. Valproic acid is an effective anti-epileptic drug; however, when taken by pregnant women to treat epilepsy, it can produce cardiac developmental defects in fetuses. In this study, the role of glycogen synthase kinase 3β in valproic acid-induced cardiac teratogenicity was investigated. Transgenic line A34 of zebrafish embryos was used at 3 days postfertilization. The results show that 78 % (18/23) of the embryos treated with 0.10 mM valproic acid (group A) had incomplete chamber formation with normal looping and 22 % (5/23) had abnormal looping. Bradycardia was also found in comparison with control embryos (P < 0.001). For the embryos treated with 0.25 mM valproic acid (group B), 92 % (22/24) demonstrated chamber formation failure and looping abnormality. Pericardial effusion, noncontracting ventricles, and enlarged, slowly beating atriums were observed at 6 days postfertilization. Valproic acid inhibited phosphorylation of serine 9 in glycogen synthase kinase 3β in a dose-dependent manner. According to immunochemical staining results, valproic acid was shown to inhibit the mass migration and proliferation of cardiomyocytes in the development of the heart-valve region through inhibition of the GSK3β Ser 9 phosphorylation. Folic acid rescued the GSK3β Ser 9 phosphorylation and reversed the valproic acid-induced cardiac morphological, functional, and biochemical defects.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes