Zhang Pei, Zhang Jie, Zhang Yexin, Wang Shuai, Pang Shuchao, Yan Bo
College of Clinical Medicine, Xinxiang Medical University, Xinxiang, Henan, China.
Division of Emergency, Jining First People's Hospital, Jining, Shandong, China.
Mol Genet Genomic Med. 2018 Nov;6(6):1209-1219. doi: 10.1002/mgg3.508. Epub 2018 Nov 8.
Coronary artery disease including acute myocardial infarction (AMI) is mainly caused by atherosclerosis, an inflammatory and metabolic disease. Autophagy has been demonstrated to play critical roles in lipid metabolism and inflammation. Altered autophagic activity has been reported in AMI patients. However, molecular basis for dysfunctional autophagy in AMI remains unexplained.
In this study, the promoter of the ATG7 gene, encoding a core protein for autophagy, was genetically and functionally analyzed in large cohorts of AMI patients (n = 355) and ethnic-matched healthy controls (n = 363). Related molecular mechanisms were also explored.
A total of 19 DNA sequence variants (DSVs) including single-nucleotide polymorphisms (SNPs) were found in the ATG7 gene promoter. Two novel DSVs and five SNPs were only identified in AMI patients group. These DSVs and SNPs, except one SNP, significantly altered the transcriptional activity of the ATG7 gene promoter in both HEK-293 and H9c2 cells (p < 0.05). Further electrophoretic mobility shift assay revealed that the DSVs and SNPs evidently affected the binding of transcription factors.
ATG7 gene DSVs and SNPs identified in AMI patients may alter the transcriptional activity of the ATG7 gene promoter and change ATG7 level, contributing to the AMI development as a rare risk factor.
包括急性心肌梗死（AMI）在内的冠状动脉疾病主要由动脉粥样硬化引起，动脉粥样硬化是一种炎症和代谢性疾病。自噬已被证明在脂质代谢和炎症中起关键作用。已有报道称AMI患者的自噬活性发生改变。然而，AMI中自噬功能障碍的分子基础仍未得到解释。
在本研究中，对编码自噬核心蛋白的ATG7基因启动子进行了基因和功能分析，研究对象为大量AMI患者队列（n = 355）和种族匹配的健康对照（n = 363）。还探索了相关的分子机制。
在ATG7基因启动子中总共发现了19个DNA序列变异（DSV），包括单核苷酸多态性（SNP）。两个新的DSV和五个SNP仅在AMI患者组中被鉴定出来。这些DSV和SNP，除了一个SNP外，在HEK-293和H9c2细胞中均显著改变了ATG7基因启动子的转录活性（p < 0.05）。进一步的电泳迁移率变动分析表明，这些DSV和SNP明显影响转录因子的结合。
在AMI患者中鉴定出的ATG7基因DSV和SNP可能会改变ATG7基因启动子的转录活性并改变ATG7水平，作为一种罕见的危险因素促成AMI的发生。
