Integrated Analysis of Microarray Data of Atherosclerotic Plaques: Modulation of the Ubiquitin-Proteasome System

Abstract

Atherosclerosis is a typical complex multi-factorial disease and many molecules at different levels and pathways were involved in its development. Some studies have investigated the dysregulation in atherosclerosis at mRNA, miRNA or DNA methylation level, respectively. However, to our knowledge, the studies that integrated these data and revealed the abnormal networks of atherosclerosis have not been reported. Using microarray technology, we analyzed the omics data in atherosclerosis at mRNA, miRNA and DNA methylation levels. Our results demonstrated that the global DNA methylation and expression of miRNA/mRNA were significantly decreased in atherosclerotic plaque than in normal vascular tissue. The interaction network constructed using the integrative data revealed many genes, cellular processes and signaling pathways which were widely considered to play crucial roles in atherosclerosis and also revealed some genes, miRNAs or signaling pathways which have not been investigated in atherosclerosis until now (e.g. miR-519d and SNTB2). Moreover, the overall protein ubiquitination in atherosclerotic plaque was significantly increased. The proteasome activity was increased early but decreased in advanced atherosclerosis. Our study revealed many classic and novel genes and miRNAs involved in atherosclerosis and indicated the effects of ubiquitin-proteasome system on atherosclerosis might be closely related to the course of atherosclerosis. However, the efficacy of proteasome inhibitors in the treatment of atherosclerosis still needs more research.

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

“…Changes in genes in the antigen processing and presentation pathway could be related to the increased uptake of modified lipoproteins by foam cells of mice under WD. The reasons for the over‐representation of genes in the ubiquitin‐mediated proteolysis pathway are not clear, though it was reported that protein ubiquitination was increased in atherosclerotic plaques, and ubiquitin‐mediated proteolysis was the most over‐represented pathway in plaques of diabetic patients 27, 28. Whereas these two pathways were the only ones affected in the 2‐week WD group, the higher number of genes differently expressed in the 14‐week WD group was reflected in 11 additional pathways significantly affected in this group (Figure 4C).…”

“…The reasons for the over-representation of genes in the ubiquitin-mediated proteolysis pathway are not clear, though it was reported that protein ubiquitination was increased in atherosclerotic plaques, and ubiquitin-mediated proteolysis was the most over-represented pathway in plaques of diabetic patients. 27,28 Whereas these two pathways were the only ones affected in the 2-week WD group, the higher number of genes differently expressed in the 14-week WD group was reflected in 11 additional pathways significantly affected in this group ( Figure 4C). Given that lesions were more developed in response to prolonged WD, but the plasma lipid profiles were similar in both WD groups, it is likely that changes in the lesional microenvironment contributed to the more-robust changes in gene expression observed in the 14-week WD group.…”

Ageing induced vascular smooth muscle cell senescence in atherosclerosis

“…Overall protein ubiquitination in atherosclerotic plaques is significantly increased, with an increase in proteasome activity in early atherosclerosis, but a decrease in advanced atherosclerosis (Wang et al . ). Proteasome inhibition can both reduce atherogenesis in mice, and protect vascular cells from oxidative stress (Dreger et al .…”

“…The global DNA hypomethylation that predominates in human atherosclerosis causes activation of a number of gene clusters (Wang et al . ; Aavik et al . ).…”

Macromolecular Degradation Systems and Cardiovascular Aging

“…117 Notably, immunoproteasome activation via the induction of proteasome subunit 8 is identified as a potential link between inflammation and apoptosis of atherosclerotic plaques. 118 However, the mechanism by which this occurs is needed to be determined in future research.…”