Yan Xiaochen, Pan Bo, Lv Tiewei, Liu Lingjuan, Zhu Jing, Shen Wen, Huang Xupei, Tian Jie
Department of Cardiology, Heart Centre, The Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Rold, Yu Zhong District, Chongqing, 400014, China.
Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.
J Biomed Sci. 2017 Jan 5;24(1):1. doi: 10.1186/s12929-016-0310-z.
Prenatal alcohol exposure may cause cardiac development defects, however, the underlying mechanisms are not yet clear. In the present study we have investigated the roles of histone modification by curcumin on alcohol induced fetal cardiac abnormalities during the development.
Q-PCR and Western blot results showed that alcohol exposure increased gene and active forms of caspase-3 and caspase-8, while decreased gene and protein of bcl-2. ChIP assay results showed that, alcohol exposure increased the acetylation of histone H3K9 near the promoter region of caspase-3 and caspase-8, and decreased the acetylation of histone H3K9 near the promoter region of bcl-2. TUNEL assay data revealed that alcohol exposure increased the apoptosis levels in the embryonic hearts. In vitro experiments demonstrated that curcumin treatment could reverse the up-regulation of active forms of caspase-3 and caspase-8, and down-regulation of bcl-2 induced by alcohol treatment. In addition, curcumin also corrected the high level of histone H3K9 acetylation induced by alcohol. Moreover, the high apoptosis level induced by alcohol was reversed after curcumin treatment in cardiac cells.
These findings indicate that histone modification may play an important role in mediating alcohol induced fetal cardiac apoptosis, possibly through the up-regulation of H3K9 acetylation near the promoter regions of apoptotic genes. Curcumin treatment may correct alcohol-mediated fetal cardiac apoptosis, suggesting that curcumin may play a protective role against alcohol abuse caused cardiac damage during pregnancy.
孕期酒精暴露可能导致心脏发育缺陷，然而，其潜在机制尚不清楚。在本研究中，我们调查了姜黄素介导的组蛋白修饰在酒精诱导的胎儿心脏发育异常中的作用。
定量聚合酶链反应（Q-PCR）和蛋白质免疫印迹结果显示，酒精暴露增加了半胱天冬酶-3（caspase-3）和半胱天冬酶-8（caspase-8）的基因表达及活性形式，同时降低了bcl-2的基因和蛋白水平。染色质免疫沉淀（ChIP）分析结果表明，酒精暴露增加了caspase-3和caspase-8启动子区域附近组蛋白H3K9的乙酰化水平，降低了bcl-2启动子区域附近组蛋白H3K9的乙酰化水平。末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）分析数据显示，酒精暴露增加了胚胎心脏中的细胞凋亡水平。体外实验表明，姜黄素处理可逆转酒精处理诱导的caspase-3和caspase-8活性形式的上调以及bcl-2的下调。此外，姜黄素还纠正了酒精诱导的组蛋白H3K9高乙酰化水平。而且，姜黄素处理后可逆转酒精诱导的心脏细胞高凋亡水平。
这些发现表明，组蛋白修饰可能在介导酒精诱导的胎儿心脏细胞凋亡中起重要作用，可能是通过上调凋亡基因启动子区域附近的H3K9乙酰化来实现的。姜黄素处理可能纠正酒精介导的胎儿心脏细胞凋亡，提示姜黄素可能对孕期酒精滥用所致的心脏损伤起到保护作用。
