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

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      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.

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      Most cited references 28

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      Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

       K Livak,  T Schmittgen (2001)
      The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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        Histone acetylation in chromatin structure and transcription.

        'The amino termini of histones extend from the nucleosomal core and are modified by acetyltransferases and deacetylases during the cell cycle. These acetylation patterns may direct histone assembly and help regulate the unfolding and activity of genes.
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          Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.

          Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.
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            Author and article information

            Affiliations
            [1 ]Department of Cardiology, the Children's Hospital of Chongqing Medical University, Chongqing, China
            [2 ]College of Biomedical Science, Center for Molecular Biology and Biotechnology, Florida Atlantic University, Boca Raton, FL 33431, USA
            Contributors
            Journal
            J Biomed Sci
            Journal of Biomedical Science
            BioMed Central
            1021-7770
            1423-0127
            2010
            10 March 2010
            : 17
            : 1
            : 16
            2841099
            1423-0127-17-16
            20219112
            10.1186/1423-0127-17-16
            Copyright ©2010 Wu et al; licensee BioMed Central Ltd.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

            Categories
            Research

            Molecular medicine

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