Thioredoxin‐interacting protein promotes activation and inflammation of monocytes with DNA demethylation in coronary artery disease

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.

DNA methylation level of the gene encoding thioredoxin-interacting protein in peripheral blood cells is associated with metabolic syndrome in the Japanese general population

“…TXNIP is an important redox regulator and plays an important role in inflammatory processes such as the activation of NLRP3 and the secretion of interleukin (IL)-1β [10,36]. The up-regulation of TXNIP expression, which is influenced by the demethylation of cg19693031, orients peripheral blood cells toward an inflammatory activated state [18]. In addition, TXNIP-mediated inflammation is closely associated with the hyperglycemic state and lipid accumulation, which are risk factors for MetS [8,36].…”

“…Particularly in white blood cells, decreased methylation at cg19693031 has been shown to be closely associated with the levels of fasting blood glucose, glycated hemoglobin A1C (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR) values, and triglycerides, and the prevalence of T2DM [13][14][15][16][17]. Depending on the decreased methylation level at cg19693031, the levels of TXNIP mRNA in white blood cells are increased, which may result in the induction of inflammation [18]. TXNIP methylation in white blood cells may play a critical role in the pathogenesis of metabolic dysfunction, given that white blood cells themselves are responsible for oxidative stress and inflammation.…”

The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

“…At-risk Takayasu arteritis, atherosclerosis, coronary artery disease, leukostasis [80,94,110,[200][201][202][203] Unstable angina pectoris, acute myocardial infarction [29,204] Diabetes associated macrovascular endothelial dysfunction [17] Diabetes associated vascular complications [19,205] TXNIP in cardiac tissue Heart attack [55] Even though a recent genetic study in a family with homozygous nonsense mutations shows that the suppression of TXNIP expression is non-lethal in humans, functional variants are reportedly associated with disease in the literature. Two different genetic variants of TXNIP can be described as genetic markers for cardiovascular risk.…”

“…In addition, the deletion of TXNIP in leucocytes is reported to reduce leukostasis [80]. In vitro studies indicate that the mRNA expressions of NLRP3, IL-1, and IL-18 are up-regulated and positively correlated with the increased TXNIP mRNA in the peripheral blood leucocytes of coronary artery disease patients or THP-1 cells [203], which is consistent with the fact that TXNIP can promote vascular inflammatory responses and accelerate the process of atherosclerosis by activating the NLRP3 inflammasome [18,48,111]. TXNIP promotes inflammation and the activation of the monocytes in association with DNA demethylation, which orientates monocytes towards an inflammatory status through the NLRP3 inflammasome pathway [203].…”

“…In vitro studies indicate that the mRNA expressions of NLRP3, IL-1, and IL-18 are up-regulated and positively correlated with the increased TXNIP mRNA in the peripheral blood leucocytes of coronary artery disease patients or THP-1 cells [203], which is consistent with the fact that TXNIP can promote vascular inflammatory responses and accelerate the process of atherosclerosis by activating the NLRP3 inflammasome [18,48,111]. TXNIP promotes inflammation and the activation of the monocytes in association with DNA demethylation, which orientates monocytes towards an inflammatory status through the NLRP3 inflammasome pathway [203]. Alternatively, one team tried to correlate TXNIP platelet content with platelet reactivity, atrial fibrillation, left atrial wall deformation, or tachycardia, but was not able to show any correlation [245][246][247][248].…”