Abstract
BackgroundAtherosclerosis is the main cause of cardiovascular diseases such as ischemic stroke and coronary heart disease. Gene-specific promoter methylation changes have been suggested as one of the causes underlying the development of atherosclerosis. We aimed to identify and validate specific genes that are differentially expressed through promoter methylation in atherosclerotic plaques. We performed the present study in four steps: (1) profiling and identification of gene-specific promoter methylation changes in atherosclerotic tissues; (2) validation of the promoter methylation changes of genes in plaques by comparison with non-plaque intima; (3) evaluation of promoter methylation status of the genes in vascular cellular components composing atherosclerotic plaques; and (4) evaluation of promoter methylation differences in genes among monocytes, T cells, and B cells isolated from the blood of ischemic stroke patients.ResultsUpon profiling, AIRE1, ALOX12, FANK1, NETO1, and SERHL2 were found to have displayed changes in promoter methylation. Of these, AIRE1 and ALOX12 displayed higher methylation levels in plaques than in non-plaque intima, but lower than those in the buffy coat of blood. Between inflammatory cells, the three genes were significantly less methylated in monocytes than in T and B cells. In the vascular cells, AIRE1 methylation was lower in endothelial and smooth muscle cells. ALOX12 methylation was higher in endothelial, but lower in smooth muscle cells. Immunofluorescence staining showed that co-localization of ALOX12 and AIRE1 was more frequent in CD14(+)-monocytes than in CD4(+)-T cell in plaque than in non-plaque intima.ConclusionsPromoter methylation changes in AIRE1 and ALOX12 occur in atherosclerosis and can be considered as novel epigenetic markers.
Highlights
Atherosclerosis is the main cause of cardiovascular diseases such as ischemic stroke and coronary heart disease
The present study was performed in four steps: (1) profiling and identification of promoter methylation changes in atherosclerotic tissues; (2) validation of promoter methylation changes of genes in plaques by comparison with non-plaque intima; (3) evaluation of promoter methylation status of genes in vascular cellular components composing atherosclerotic plaques; and (4) evaluation of promoter methylation differences between inflammatory cell types infiltrated into atherosclerotic plaques (Fig. 1)
Profiling and identification of gene-specific promoter methylation changes in carotid endarterectomy (CEA) plaques In the first step of the present study, we initially identified 3275 sequenced tags uniquely mapped to CEA plaques after methylated-CpG island amplification (MCA)
Summary
Atherosclerosis is the main cause of cardiovascular diseases such as ischemic stroke and coronary heart disease. Gene-specific promoter methylation changes have been suggested as one of the causes underlying the development of atherosclerosis. Atherosclerosis is the primary cause of cardiovascular diseases including ischemic stroke and coronary heart disease [1]. Demographic characteristics such as age, sex, and race and established risk factors such as hypertension, diabetes, hyperlipidemia, and smoking are considered predictive markers for atherosclerosis and cardiovascular diseases [2]. The effect of environmental factors and aging on the development of atherosclerosis has been difficult to investigate owing to the known risk factors and specific genetic polymorphisms. The genespecific promoter methylation causally related with the pathogenesis of atherosclerosis are still insufficient to explain the epigenetic pathomechanisms in the development of the disease [10, 14, 15]
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