Abstract 511: Thioredoxin Interacting Protein Ablation Protects Vascular Smooth Muscle Cells from Oxidative Stress

Abstract

Vascular smooth muscle cells (SMC) play an important role in atherosclerosis. In response to increased oxidative stress, SMC secrete cytokines and express cell adhesion molecules which in turns, regulate monocyte/macrophage adhesion and other processes during atherosclerosis. Thioredoxin interacting protein (Txnip), an endogenous inhibitor of thioredoxin, is a key regulator of cellular sulfhydryl redox status. Recent studies also showed that Txnip is a key modulator of cellular glucose metabolism and insulin resistance. In addition, Txnip serves as a critical sensor linking inflammasome to inflammation associated oxidative stress. We hypothesized that Txnip ablation would lead to decreased inflammatory responses in SMC by limiting cellular oxidative stress. To examine this hypothesis, we isolated primary SMC from the thoracic aorta of Txnip knockout (TKO) mice. Comparing to SMC from wild type (WT) control mice, SMC from TKO mice have reduced levels of reactive oxygen species (ROS), as assessed by dihydroethidium (DHE) staining. Furthermore, Txnip ablation protected cells from oxidative stress when challenged with OxPAPC and hydrogen peroxide. Inflammatory markers (ICAM-1 and MCP-1) were down-regulated in Txnip-null SMC whereas oxidative stress-induced expression of inflammatory markers was inhibited by Txnip-deficiency. Interestingly, we found that macrophage adhesion to SMC was markedly reduced in Txnip-null cells. This is associated with a reduction in adhesion molecule and inflammatory marker expression in both SMC and macrophages from TKO mice. SMC from TKO mice exhibited an increased expression of KLF2 and decreased NF-κB (p65) activity, comparing to WT SMC. Taken together, our data demonstrate a critical role of Txnip-deficiency in inflammatory responses in SMC and suggest Txnip inhibition in SMC may represent a potential target for intervention of atherosclerosis.