Alcohol-induced histone H3K9 hyperacetylation and cardiac hypertrophy are reversed by a histone acetylases inhibitor anacardic acid in developing murine hearts
Alcohol-induced histone H3K9 hyperacetylation and cardiac hypertrophy are reversed by a histone acetylases inhibitor anacardic acid in developing murine hearts
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在发育中的小鼠心脏中，组蛋白乙酰化酶抑制剂漆树酸可逆转酒精诱导的组蛋白 H3K9 过度乙酰化和心脏肥大
DOI：
10.1016/j.biochi.2015.03.012
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发表时间：
2015-06-01
期刊：
影响因子：
3.9
通讯作者：
Tian, Jie
中科院分区：
文献类型：
--
作者：
Peng, Chang;Zhang, Weihua;Tian, Jie
背景：心脏基因的表达受到精确调控，任何干扰都可能导致发育缺陷。在之前的一项研究中，我们证明了怀孕期间饮酒可能导致心脏基因的不受控制的表达，最终导致心脏发育不良。然而，其潜在机制仍不清楚。本研究旨在探讨酒精性心肌肥厚的发生机制。方法和结果：用56%乙醇或生理盐水灌胃C57 BL/6孕鼠，取胎鼠心脏进行分析。在暴露于酒精的胎鼠心脏中，p300、CBP、PCAF、SRC 1与NKX2.5启动子的结合增加，但GCN 5除外。在相同的样本中观察到H3 K9的乙酰化增加以及NKX 2.5、β-MHC和Cx43的mRNA表达增加。用泛乙酰化酶抑制剂漆树酸处理降低了p300和PCAF对NKX2.5、β-MHC、Cx43启动子的结合亲和力，并减弱了H3 K9的过度乙酰化。有趣的是，漆树酸下调这些心脏基因的过度表达诱导的酒精和最终衰减乙醇诱导的胎儿mice.Conclusions心脏肥大：我们的研究结果表明，在怀孕期间暴露于酒精可能会导致胎儿心脏肥大。p300和PCAF介导的NKX2.5、Cx43的过度表达可能是酒精诱导心肌肥厚的重要机制。漆树酸可下调心脏基因的过表达，逆转妊娠小鼠乙醇处理引起的心脏肥大，提示漆树酸可能是治疗心脏肥大的潜在药物。(C)2015 Elsevier B. V.和法国生物化学与生物分子学会（SFBBM）。All rights reserved.
Background: The expression of cardiac genes is precisely regulated, and any perturbation may cause developmental defects. In a previous study, we demonstrated that alcohol consumption during pregnancy could lead to uncontrolled expressions of cardiac genes and eventually result in cardiac dysplasia. However, the underlying mechanisms remain unclear. In the present study, we have investigated the alcohol-induced cardiac hypertrophy and its potential mechanisms. Furthermore, the protective effect of anacardic acid against the alcohol-induced cardiac hypertrophy has been explored in experimental mice.Methods and results: C57BL/6 pregnant mice were gavaged with 56% ethanol or saline and the hearts of their fetus were collected for analysis. Binding of p300, CBP, PCAF, SRC1, except GCN5, were increased to the NKX2.5 promoter in fetal mouse hearts exposed to alcohol. Increased acetylation of H3K9 and increased mRNA expression of NKX2.5,beta-MHC and Cx43 were observed in the same samples. Treatment with a pan-acetylase inhibitor, anacardic acid, reduced the binding affinity of p300 and PCAF to the NKX2.5, beta-MHC, Cx43 promoters and attenuated H3K9 hyperacetylation. Interestingly, anacardic acid down-regulated over-expression of these cardiac genes induced by alcohol and ultimately attenuated ethanol-induced cardiac hypertrophy in fetal mice.Conclusions: Our results indicate that alcohol exposure during pregnancy could lead to fetal cardiac hypertrophy. The over-expression of NKX2.5, Cx43 mediated by p300 and PCAF may be critical mechanisms of alcohol-induced cardiac hypertrophy. Anacardic acid can down-regulate the overexpression of cardiac genes and reverse cardiac hypertrophy caused by alcohol treatment in pregnant mice, suggesting it could be a potential therapeutic agent for the treatment of cardiac hypertrophy. (C) 2015 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.