Abstract
BackgroundCoronary 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.MethodsIn 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.ResultsA 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.Conclusions 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.
Highlights
Coronary artery disease (CAD) including acute myocardial infarction (AMI) is a common complex disease that is caused by atherosclerosis, an inflammatory and metabolic disease
Previous studies have shown that the polymorphism (V471A) in ATG7 gene that substitutes alanine for valine has been significantly associated with an earlier onset of Huntington’s disease (HD) (Metzger et al, 2010)
Lower and elevated ATG7 levels have been observed in the patients with ulcerative colitis and active eosinophilic esophagitis, respectively (Lankarani, Sepehrimanesh, Seghatoleslam, Hoseini, & Ghavami, 2017; Merves et al, 2016)
Summary
Coronary artery disease (CAD) including acute myocardial infarction (AMI) is a common complex disease that is caused by atherosclerosis, an inflammatory and metabolic disease. Genome‐wide association studies have revealed a great number of genetic loci for CAD and AMI, some of which are associated with lipid metabolism and inflammation. Tissue‐specific deletion of ATG7 gene and subsequent defective autophagy has been widely studied, including cardiomyocytes, vascular endothelial cells, and smooth muscle cells. In vascular smooth muscle cells, ATG7 gene deletion alters contractility and Ca2+ homeostasis (Michiels, Fransen, De Munck, De Meyer, & Martinet, 2015). We have reported altered autophagic activity in CAD and AMI patients by examining LC3 gene expression levels (Wu, Wei et al, 2011; Wu, Liu et al, 2011). As ATG7 is one of core proteins for autophagy, we postulated that dysregulated ATG7 gene expression may lead to altered autophagic activity, playing an important role in the development of CAD and AMI. We genetically and functionally analyzed the promoter of ATG7 gene in large cohort of AMI patients and ethnic‐matched healthy controls
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