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Disruption of Planar Cell Polarity Pathway Attributable to Valproic Acid-Induced Congenital Heart Disease through Hdac3 Participation in Mice / 中华医学杂志(英文版)
Chinese Medical Journal ; (24): 2080-2088, 2018.
Article in English | WPRIM | ID: wpr-773923
ABSTRACT
Background@#Valproic acid (VPA) exposure during pregnancy has been proven to contribute to congenital heart disease (CHD). Our previous findings implied that disruption of planar cell polarity (PCP) signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase (HDAC) inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes (Vangl2/Scrib/Rac1), subsequently screening out the specific HDACs regulating PCP pathway.@*Methods@#VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day 10.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells (undifferentiated rat cardiomyoblasts) were transfected with Hdac1/2/3 specific small interfering RNA (siRNA). Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Rac1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay.@*Results@#VPA could induce CHD (P 0.05); VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity (P 0.05).@*Conclusion@#VPA could inhibit Hdac1/2/3, Vangl2/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.
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Full text: Available Index: WPRIM (Western Pacific) Main subject: Physiology / Transfection / Embryology / Valproic Acid / Cell Polarity / Enzyme Inhibitors / Histone Deacetylase Inhibitors / Fetal Heart / Heart Defects, Congenital / Histone Deacetylases Type of study: Prognostic study Limits: Animals / Pregnancy Language: English Journal: Chinese Medical Journal Year: 2018 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Physiology / Transfection / Embryology / Valproic Acid / Cell Polarity / Enzyme Inhibitors / Histone Deacetylase Inhibitors / Fetal Heart / Heart Defects, Congenital / Histone Deacetylases Type of study: Prognostic study Limits: Animals / Pregnancy Language: English Journal: Chinese Medical Journal Year: 2018 Type: Article