Thioredoxin1 downregulates oxidized low-density lipoprotein-induced adhesion molecule expression via Smad3 protein

PLoS One. 2013 Sep 23;8(9):e76226. doi: 10.1371/journal.pone.0076226. eCollection 2013.

Abstract

Atherosclerosis is a chronic inflammation disease that is initiated by endothelial cell injury. Oxidized low-density lipoprotein (ox-LDL) is directly associated with chronic vascular inflammation. To understand whether thioredoxin1 (Trx1) participates in an antiinflammatory defense mechanism in atherosclerosis, we investigated the effect of Trx1 on the expression of two adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), in human umbilical vein endothelial cells (HUVECs). Thioredoxin1 and dominant-negative mutant thioredoxin1 (TD) were transiently overexpressed using adenovirus vector gene transfer. Our data showed that Trx1 overexpression suppressed ox-LDL-induced adhesion molecule expression in HUVECs. The overexpression of Trx1 promoted ox-LDL-induced Smad3 phosphorylation and nuclear translocation. A co-immunoprecipitation assay indicated that Smad3 continued to interact with Trx1 with or without ox-LDL stimulation. These results suggest that Trx1 inherently suppresses VCAM-1 and ICAM-1 expression in vascular endothelia and may prevent the initiation of atherosclerosis by attenuating adhesion molecule expression. The enhancement of Smad3 phosphorylation and nuclear expression appears to be primarily responsible for the Trx1-induced downregulation of adhesion molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Analysis of Variance
  • Atherosclerosis / metabolism
  • Atherosclerosis / physiopathology*
  • Blotting, Western
  • Cell Adhesion Molecules / metabolism*
  • Gene Expression Regulation / physiology*
  • Gene Knockdown Techniques
  • Gene Transfer Techniques
  • Genetic Vectors / genetics
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Lipoproteins, LDL / metabolism*
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Smad3 Protein / metabolism*
  • Thioredoxins / metabolism*

Substances

  • Cell Adhesion Molecules
  • Lipoproteins, LDL
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • SMAD3 protein, human
  • Smad3 Protein
  • TXN protein, human
  • oxidized low density lipoprotein
  • Thioredoxins

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (no. 30900627, 81270379, 81200221). The funding agency had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.