PUBLICATION
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
- Authors
- Yu, W.H., Ho, Y.L., Huang, P.T., Chu, S.L., Tsai, H.J., Liou, H.H.
- ID
- ZDB-PUB-150301-8
- Date
- 2016
- Source
- Cardiovascular Toxicology 16(1): 34-45 (Journal)
- Registered Authors
- Tsai, Huai-Jen
- Keywords
- 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
- PubMed
- 25724324 Full text @ Cardiovasc. Toxicol.
Citation
Yu, W.H., Ho, Y.L., Huang, P.T., Chu, S.L., Tsai, H.J., Liou, H.H. (2016) 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. Cardiovascular Toxicology. 16(1):34-45.
Abstract
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping