氨基酸降低介导组蛋白乙酰化致先天性心脏病发病机制研究

Congenital heart diseases (CHD) are the most common malformations in China. The increased prevalence has severely influenced the health of children and the development of economics. So for, their pathogenesis has not been well clarified. In previous study we demonstrated that the most of amino acids (including arginine family, aromatic and branched-chain amino acid) associated with P300 and IGF1R (insulin-like growth factor type 1 receptor) were decreased in the amniotic fluid affected with CHD. Then we cultured the H9C2 cells with half concentration of amino acids, and found the decrease of P300 and the histone acetylases activity, as well as the reduced IGF1R expression and the decreased histone acetylases in IGF1R promoter region. We will go further study to clarify the mechanism of arginine family, aromatic and branched-chain amino acid in CHD using in vivo and in vitro experiments. Besides, we will enlarge the samples to measure amino acids, P300 and IGF1R proteins in amniotic fluid of CHD. Therefore, we will demonstrate that the reduced amino acid is one of the important risk factors for CHD, and clarify that amino acid regulating IGFIR via epigenetic mechanisms is one of the important mechanisms in CHD. Thus, we may provide a new way for the early diagnosis and prevention of CHD.

先天性心脏病(简称先心病)是我国最常见的出生缺陷，严重影响着婴幼儿健康及人口素质，目前其患病机制并不十分明确。我们前期研究发现先心病胎儿羊水中氨基酸明显降低（包括精氨酸家族、芳香族氨基酸及支链氨基酸），P300及IGF1R（类胰岛素生长因子1型受体）蛋白显著下降；并在用低氨基酸培养大鼠心肌细胞H9C2后发现P300降低，组蛋白乙酰化活性明显下降，IGF1R表达下调，且其启动子区乙酰化水平降低。本项目拟在这些研究基础上利用细胞、动物实验进一步探索精氨酸家族、芳香族及支链氨基酸在先心病发病的作用机制，并扩大样本检测先心病胎儿羊水中氨基酸及P300与IGF1R蛋白含量，明确氨基酸降低是先心病的重要危险因素，并阐明氨基酸降低通过表观遗传方式调节IGFIR是其致先心病的重要机制之一，为先心病的早期诊断及预防奠定一定的理论基础。

先天性心脏病(简称先心病)是我国最常见的出生缺陷，严重影响着婴幼儿健康及人口素质，目前其患病机制并不十分明确。本项目利用液相串联质谱检测先心病胎儿羊水中氨基酸含量及IGF（类胰岛素生长因子）系统和表观遗传相关蛋白含量，并利用1/2浓度的氨基酸（1/2AA）处理心肌H9C2细胞。发现先心病胎儿羊水中氨基酸含量明显下降，下降幅度从58.9%到21.4%，共14种氨基酸（Ala, Phe, Val, Tyr, Arg, Asp, Glu, Trp, Cit, Leu, Thr, Gln, His and Gly）明显下降，前9种下降幅度约50%（从58.9% 到 42.9%），与此同时，羊水中P300及IGF1R（类胰岛素生长因子1型受体）蛋白含量显著下降。1/2AA处理细胞后，发现P300及IGF1R表达下调，组蛋白乙酰化活性明显下降以及IGF1R启动子区乙酰化水平也明显降低。再者，统计4819例遗传代谢病筛查结果，分析发现氨基酸类遗传代谢病占所有筛查儿童的0.77%，占所有诊断病种的42%。此外，揭示了半胱氨酸这种氨基酸作为先心病的重要危险因子的部分作用机制，半胱氨酸是通过增强 KLHL3介导的泛素化使cMyBP-C表达下降，继而影响心脏发育的。

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