TAILIEUCHUNG - Sodium valproate-induced congenital cardiac abnormalities in mice are associated with the inhibition of histone deacetylase

Valproic acid, a widely used anticonvulsant drug, is a potent teratogen resulting in various congenital abnormalities. However, the mechanisms underlying valproic acid induced teratogenesis are nor clear. Recent studies indicate that histone deacetylase is a direct target of valproic acid. Methods: In the present study, we have used histological analysis and RT-PCR assays to examine the cardiac abnormalities in mice treated with sodium valproate (NaVP) and determined the effects of NaVP on histone deacetylase activity and the expression. | Wu et al. Journal of Biomedical Science 2010 17 16 http content 17 1 16 I NSC The cost of publication in Journal of Biomedical Science is bourne by the National Science Council Taiwan. JOURNAL OF BIOMEDICAL SCIENCE RESEARCH Open Access Sodium valproate-induced congenital cardiac abnormalities in mice are associated with the inhibition of histone deacetylase Gang Wu 1 2 Changlong Nan2 Johnathon C Rollo2 Xupei Huang2 and Jie Tian 1 Abstract Background Valproic acid a widely used anticonvulsant drug is a potent teratogen resulting in various congenital abnormalities. However the mechanisms underlying valproic acid induced teratogenesis are nor clear. Recent studies indicate that histone deacetylase is a direct target of valproic acid. Methods In the present study we have used histological analysis and RT-PCR assays to examine the cardiac abnormalities in mice treated with sodium valproate NaVP and determined the effects of NaVP on histone deacetylase activity and the expression of heart development-related genes in mouse myocardial cells. Results The experimental data show that NaVP can induce cardiac abnormalities in fetal mice in a dose-dependent manner. NaVP causes a dose-dependent inhibition of hitone deacetylase HDAC activity in mouse myocardial cells. However the expression levels of HDAC both HDAC1 and HDAC2 are not significantly changed in fetal mouse hearts after administration of NaVP in pregnant mice. The transcriptional levels of other heart development-related genes such as CHF1 Tbx5 and MEF2 are significantly increased in fetal mouse hearts treated with NaVP Conclusions The study indicates that administration of NaVP in pregnant mice can result in various cardiac abnormalities in fetal hearts which is associated with an inhibition of histone deacetylase without altering the transcription of this enzyme. Introduction Valproic acid VPA has been widely used as an anticonvulsant drug for over 40 years. It is unusual among anticonvulsants .

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