Thioredoxin 1 downregulates MCP-1 secretion and expression in human endothelial cells by suppressing nuclear translocation of activator protein 1 and redox factor-1

Abstract

To know whether thioredoxin 1 (Trx1) works for an antioxidant defense mechanism in atherosclerosis, the effect of Trx1 on the release of monocyte chemoattractant protein-1 (MCP-1), a potent chemoattractant for recruitment and accumulation of monocytes/macrophages in the intima of artery vessel, was investigated in human endothelial-like EA.hy 926 cells. It was found that overexpression of Trx1 suppressed, whereas knockdown of endogenous Trx1 enhanced, oxidized low-density lipoprotein (oxLDL)-stimulated MCP-1 release and expression in the cells. It was also observed that overexpression of Trx1 suppressed, whereas depletion of endogenous Trx1 greatly promoted, nuclear translocation of c-Jun and the redox factor-1 (Ref-1). Electrophoretic mobility shift assay showed significantly reduced DNA-binding activity of activator protein-1 (AP-1) in Trx1-overexpressing cells but apparently enhanced DNA binding activity of AP-1 in Trx1-knockdown cells, indicating that nuclear Ref-1 rather than Trx1 itself finally dominates the regulation of AP-1 activity, although Trx1 is considered to upregulate AP-1 activity. It was also observed that Trx1 depressed intracellular generation of reactive oxygen species (ROS). Diphenyleneiodonium (DPI), the inhibitor of NADPH oxidase, suppressed MCP-1 secretion, whereas transient expression of Nox1 enhanced transcription of MCP-1 in endothelial cells. Assays with AP-1 and MCP-1 luciferase reporters further demonstrated that transient expression of Trx1 significantly depressed the transcriptional activity of c-Jun/c-Fos and consequent MCP-1 transcription. This study suggests that Trx1 inherently suppresses MCP-1 expression in vascular endothelium and may prevent atherosclerosis by depressing MCP-1 release. Besides the suppression of intracellular ROS generation, the inhibition of nuclear translocation of AP-1 and Ref-1 are mainly responsible for the downregulation of MCP-1 by Trx1.

Molecular Biology of Atherosclerosis

“…Because the predominant effects on atherosclerosis for Nrf2 KO seem to relate to foam cell formation, results of these studies are included in Among the most important antioxidant defense mechanisms is the Trx-TrxR system. Trx has a dual role as an antioxidant enzyme (capable of regenerating reduced cysteine from protein cysteine disulfide bonds and reducing sulfenic acid) and as a redox-dependent inhibitor of ASK1 (289). Importantly, in oxidizing conditions, Trx is bound by thioredoxin-interacting protein (TXNIP) through disulfide linkage, allowing ASK1 to activate the JNK pathway.…”

Thioredoxin-1 Promotes Anti-Inflammatory Macrophages of the M2 Phenotype and Antagonizes Atherosclerosis

“…45 Moreover, Trx-1 downregulates MCP-1 expression and secretion in oxidized low-density lipoprotein-stimulated human endothelial cells by suppressing nuclear translocation of AP-1 and redox factor-1. 46 Therefore, we hypothesized that, on the one hand, Trx-1 might induce macrophage polarization into the …”

Thioredoxin-1 Attenuates Early Graft Loss after Intraportal Islet Transplantation in Mice

“…TRX has been reported to effectively suppress oxidative stress [32]. Moreover, it also exhibited anti-inflammatory and anti-apoptotic effects in various experimental models [15][16][17][18]. Therefore, we examined the effects of TRX on early graft loss after islet transplantation.…”

“…TRX protects cells against oxidative stress by scavenging reactive oxygen species, and exerts anti-inflammatory and antiapoptotic effects by regulating cytokines, signaling molecules and transcription factors [15][16][17][18]. In addition, TRX regulates neutrophil activation and chemotaxis by acting directly on neutrophils [19][20][21].…”