Up-regulation of thioredoxin interacting protein (Txnip) by p38 MAPK and FOXO1 contributes to the impaired thioredoxin activity and increased ROS in glucose-treated endothelial cells

Biochem Biophys Res Commun. 2009 Apr 17;381(4):660-5. doi: 10.1016/j.bbrc.2009.02.132. Epub 2009 Feb 28.


Oxidative stress induced by hyperglycemia is a key factor in the development of cardiovascular diseases in diabetes. Thioredoxin (Trx) system, a major thiol antioxidant system, regulates the reduction of intracellular reactive oxygen species (ROS). In this study, we demonstrated that high glucose significantly increased intracellular ROS levels in human aortic endothelial cells (HAECs). Additionally, high glucose reduced the antioxidant activity of thioredoxin. To investigate the mechanisms involved, we found that glucose enhanced the expression of thioredoxin interacting protein (Txnip), a Trx inhibitory protein, through p38 mitogen-activated protein kinase (MAPK). We also showed that glucose regulated Txnip at transcription level and p38 MAPK and forkhead box O1 transcriptional factor (FOXO1) were involved in the process. Taken together, upregulation of Txnip and subsequent impairment of thioredoxin antioxidative system through p38 MAPK and FOXO1 may represent a novel mechanism for glucose-induced increase in intracellular ROS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism*
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Humans
  • Reactive Oxygen Species / metabolism*
  • Thioredoxins / metabolism*
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Carrier Proteins
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Reactive Oxygen Species
  • TXNIP protein, human
  • Thioredoxins
  • p38 Mitogen-Activated Protein Kinases
  • Glucose