Sodium valproate-induced congenital cardiac abnormalities in mice are associated with the inhibition of histone deacetylase.
Sodium valproate-induced congenital cardiac abnormalities in mice are associated with the inhibition of histone deacetylase.
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DOI：
10.1186/1423-0127-17-16
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发表时间：
2010-03-10
影响因子：
11
通讯作者：
Tian J
中科院分区：
文献类型：
--
作者：
Wu G;Nan C;Rollo JC;Huang X;Tian J
丙戊酸是一种广泛使用的抗惊厥药物，是一种强致畸剂，可导致各种先天性畸形。然而，丙戊酸诱导致畸的机制尚不清楚。最近的研究表明，组蛋白去乙酰化酶是丙戊酸的直接靶点。在本研究中，我们已经使用组织学分析和RT-PCR分析，以检查心脏异常小鼠与丙戊酸钠（NaVP）治疗，并确定NaVP对组蛋白去乙酰化酶活性和心脏发育相关基因的表达在小鼠心肌细胞中的影响。实验数据表明，NaVP可以以剂量依赖的方式诱导胎鼠心脏异常。NaVP对小鼠心肌细胞中的hitone deacetylase（HDAC）活性产生剂量依赖性抑制。然而，妊娠小鼠给予NaVP后，胎鼠心脏中HDAC（HDAC 1和HDAC 2）的表达水平没有显著变化。其他心脏发育相关基因的转录水平，如CHF 1，Tbx 5和MEF 2，在用NaVP处理的胎鼠心脏中显著增加。该研究表明，在妊娠小鼠中给予NaVP可导致胎儿心脏的各种心脏异常，这与组蛋白脱乙酰酶的抑制有关，而不改变该酶的转录。
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. 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. 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. 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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影响因子：
3.1
作者：
Alsdorf, Rachel;Wyszynski, Diego F
通讯作者：
Wyszynski, Diego F
影响因子：
2.6
作者：
Riedel, B;Jia, YY;Huang, XP
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DOI：
10.1073/pnas.252648999
发表时间：
2002-12-10
影响因子：
11.1
作者：
Sakata, Y;Kamei, CN;Chin, MT
通讯作者：
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影响因子：
56.9
作者：
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