Shi Jin, Zhao Weian, Pan Bo, Zheng Min, Si Lina, Zhu Jing, Liu Lingjuan, Tian Jie
Heart Centre, Children's Hospital of Chongqing Medical University, Chongqing, China.
Key Laboratory of Developmental Disease in Childhood, Ministry of Education, Chongqing Medical University, Chongqing, China.
Alcohol Clin Exp Res. 2017 Jan;41(1):87-95. doi: 10.1111/acer.13273. Epub 2016 Nov 24.
Abusive alcohol utilization of pregnant woman may cause congenital heart disease (CHD) of fetus, where alcohol ignites histone H3 hyperacetylation leading to abnormal development of heart morphogenesis and associated genes. Knowledge about the regularized upstream genes is little, but bone morphogenetic protein (BMP) signaling may actively and prominently take part in alteration in acetylation of histone H3. The supreme objective of this study was to unearth the involvement of BMP signaling pathway in alcohol-driven hyperacetylation of histone H3 in cardiomyoblast cells.
Cardiomyoblast cells (H9c2 cells) were addicted with alcohol (100 mM) for 24 hours. Dorsomorphin (5 μM) was used for the inhibition of BMP signaling pathway. We detected the phosphorylation activity of SMAD1/5/8, mRNA expression, histone acetyltransferases (HAT)/histone deacetylase (HDAC) activity, and acetylation of histone H3.
Following alcohol exposure, phosphorylation of SMAD1/5/8 and HAT activities was increased to a significant extent, while histone H3 acetylation and expression of heart development-related genes were also increased. The said phenomenon influenced by alcohol was reverted upon dorsomorphin treatment to the cells without effecting HDAC activity.
The data clearly identified that BMP-mediated histone H3 acetylation of heart development-related genes might be one of the possible cellular mechanisms to control alcohol-induced expression of heart development-related genes. Dorsomorphin, on the other hand, may modulate alcohol-induced hyperacetylation of histone H3 through BMP targeting, which could be a potential way to block CHD.
孕妇滥用酒精可能导致胎儿先天性心脏病（CHD），酒精会引发组蛋白H3高乙酰化，导致心脏形态发生及相关基因的异常发育。关于调控上游基因的了解较少，但骨形态发生蛋白（BMP）信号可能积极且显著地参与组蛋白H3乙酰化的改变。本研究的主要目的是揭示BMP信号通路在酒精驱动的心肌成纤维细胞组蛋白H3高乙酰化中的作用。
将心肌成纤维细胞（H9c2细胞）用酒精（100 mM）处理24小时。使用多斯吗啡（5 μM）抑制BMP信号通路。我们检测了SMAD1/5/8的磷酸化活性、mRNA表达、组蛋白乙酰转移酶（HAT）/组蛋白去乙酰化酶（HDAC）活性以及组蛋白H3的乙酰化。
酒精处理后，SMAD1/5/8的磷酸化和HAT活性显著增加，同时组蛋白H3乙酰化及心脏发育相关基因的表达也增加。多斯吗啡处理细胞后，酒精诱导的上述现象恢复，且不影响HDAC活性。
数据明确表明，BMP介导的心脏发育相关基因的组蛋白H3乙酰化可能是控制酒精诱导的心脏发育相关基因表达的一种可能的细胞机制。另一方面，多斯吗啡可能通过靶向BMP调节酒精诱导的组蛋白H3高乙酰化，这可能是阻断先天性心脏病的一种潜在方法。
