Abstract
Numerous studies have demonstrated that thioredoxin‐interacting protein (TXNIP) expression of peripheral blood leucocytes is increased in coronary artery disease (CAD). However, the molecular mechanism of this phenomenon remained unclear. DNA methylation plays important roles in the regulation of gene expression. Therefore, we speculated there might be a close association between the expression of TXNIP and methylation. In this study, we found that compared with controls, DNA methylation at cg19693031 was decreased in CAD, while mRNA expressions of TXNIP and inflammatory factors, NLRP3, IL‐1β, IL‐18, were increased. Methylation at cg19693031 was negatively associated with TXNIP expression in the cohort, THP‐1 and macrophages/foam cells. Furthermore, Transwell assay and co‐cultured adhesion assay were performed to investigate functions of TXNIP on the migration of THP‐1 or the adhesion of THP‐1 on the surface of endothelial cells, respectively. Notably, overexpressed TXNIP promoted the migration and adhesion of THP‐1 cells and expressions of NLRP3, IL‐18 and IL‐1β. Oppositely, knock‐down TXNIP inhibited the migration and adhesion of THP‐1 and expressions of NLRP3, IL‐18. In conclusion, increased TXNIP expression, related to cg19693031 demethylation orientates monocytes towards an inflammatory status through the NLRP3 inflammasome pathway involved in the development of CAD.
Highlights
Despite advances in prevention and treatment,[1,2] coronary artery disease (CAD) remains a threat to human health worldwide[3,4] due to atherosclerosis (AS) and its thrombotic complications
The results of the bisulphite sequencing and quantitative polymerase chain reaction (qPCR) showed that decreased methylation level of cg19693031 and increased thioredoxin-interacting protein (TXNIP) mRNA expression were found in the THP-1 cells treated with 5-azacytidine; there were statistically significant differences among groups treated with different dosages of 5-azacytidine (Figure 1G,H)
Our results indicated that the mRNA expression of NLRP3, IL-1β and IL-18 was up-regulated and positively correlated with the increased TXNIP in the peripheral blood leucocytes (PBLs) of CAD and THP-1 cells, which is consistent with that TXNIP could promote vascular inflammatory responses and accelerate the process of AS by activating NLRP3 inflammasome.[30-32]
Summary
Despite advances in prevention and treatment,[1,2] coronary artery disease (CAD) remains a threat to human health worldwide[3,4] due to atherosclerosis (AS) and its thrombotic complications. Numerous evidences have demonstrated that DNA methylation, an important epigenetic modification, could regulate gene expression and involve in various biological and pathological processes, including CAD.[5,6]. Coronary artery disease was considered to be caused by a series of inflammatory procedures and promoted by oxidative stress.[10,11]. Depending on the accumulation of ROS and generation of oxidative stress, TXNIP plays important roles in inflammatory responses[14] and cell apoptosis.[15]. TXNIP could bind to the NOD-like receptor family, pyrin domain containing 3 (NLRP3) in response to oxidative stress and activate the NLRP3inflammasome to regulate inflammation, which contributes to diabetes and Alzheimer's disease.[16,17]. Combined with our previous study,[23] we hypothesized that overexpressed TXNIP regulated by demethylated cg19693031 might play important role in the inflammatory responses and activation of monocytes, which provided compelling evidences for TXNIP serving as a risk factor for CAD. We executed the following study to explore the function of TXNIP in CAD
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