Peng Chang, Zhang Weihua, Zhao Weian, Zhu Jing, Huang Xupei, Tian Jie
Heart Center, Children's Hospital of Chongqing Medical University, Chongqing, PR China; Key Laboratory of Pediatrics in Chongqing, Chongqing, PR China.
Key Laboratory of Pediatrics in Chongqing, Chongqing, PR China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, PR China.
Biochimie. 2015 Jun;113:1-9. doi: 10.1016/j.biochi.2015.03.012. Epub 2015 Mar 20.
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.
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, β-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, β-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.
Our results indicate that alcohol exposure during pregnancy could lead to fetal cardiac hypertrophy. The over-expression of NKX2.5, β-MHC, Cx43 mediated by p300 and PCAF may be critical mechanisms of alcohol-induced cardiac hypertrophy. Anacardic acid can down-regulate the over-expression 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.
心脏基因的表达受到精确调控，任何扰动都可能导致发育缺陷。在先前的一项研究中，我们证明孕期饮酒会导致心脏基因的表达失控，最终导致心脏发育异常。然而，其潜在机制仍不清楚。在本研究中，我们调查了酒精诱导的心脏肥大及其潜在机制。此外，还在实验小鼠中探索了没食子酸对酒精诱导的心脏肥大的保护作用。
给C57BL/6孕鼠灌胃56%乙醇或生理盐水，并收集其胎儿的心脏进行分析。在暴露于酒精的胎鼠心脏中，p300、CBP、PCAF、SRC1（除GCN5外）与NKX2.5启动子的结合增加。在相同样本中观察到H3K9乙酰化增加以及NKX2.5、β-MHC和Cx43的mRNA表达增加。用泛乙酰化酶抑制剂没食子酸处理可降低p300和PCAF与NKX2.5、β-MHC、Cx43启动子的结合亲和力，并减弱H3K9高乙酰化。有趣的是，没食子酸下调了酒精诱导的这些心脏基因的过表达，并最终减轻了胎鼠乙醇诱导的心脏肥大。
我们的结果表明孕期暴露于酒精可导致胎儿心脏肥大。由p300和PCAF介导的NKX2.5、β-MHC、Cx43的过表达可能是酒精诱导心脏肥大的关键机制。没食子酸可下调心脏基因的过表达，并逆转孕鼠酒精处理引起的心脏肥大，表明它可能是治疗心脏肥大的潜在治疗药物。
