title: Thioredoxin interacting protein promotes endothelial cell inflammation in response to disturbed flow by increasing leukocyte adhesion and repressing Kruppel-like factor 2.
abstract: BACKGROUND
  Endothelial cells (EC) at regions exposed to disturbed flow (d-flow) are predisposed to inflammation and the subsequent development of atherosclerosis. We previously showed that thioredoxin interacting protein (TXNIP) was required for tumor necrosis factor-mediated expression of vascular cell adhesion molecule-1.
  
  
  OBJECTIVE
  We sought to investigate the role of TXNIP in d-flow-induced cell adhesion molecule expression and leukocyte interaction with vessels, and the mechanisms by which TXNIP suppresses athero-protective gene expression.
  
  
  RESULTS
  Using en face staining of mouse aorta, we found a dramatic increase of TXNIP in EC at sites exposed to d-flow as compared to steady flow. EC-specific TXNIP (EC-TXNIP) knockout mice showed significant decreases in vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 mRNA expression in the d-flow regions of mouse aorta. Intravital microscopy of mesenteric venules showed that leukocyte rolling time was decreased, whereas rolling velocity was increased significantly in EC-TXNIP knockout mice. In vitro experiments using a cutout flow chamber to generate varying flow patterns showed that increased TXNIP was required for d-flow-induced EC-monocyte adhesion. Furthermore, we found that the expression of Kruppel-like factor 2, a key anti-inflammatory transcription factor in EC, was inhibited by TXNIP. Luciferase and chromatin immunoprecipitation assays showed that TXNIP was present within a repressing complex on the Kruppel-like factor 2 promoter.
  
  
  CONCLUSIONS
  These data demonstrate the essential role for TXNIP in mediating EC-leukocyte adhesion under d-flow, as well as define a novel mechanism by which TXNIP acts as a transcriptional corepressor to regulate Kruppel-like factor 2-dependent gene expression.
authors.affiliation: Aab Cardiovascular Research Institute, 601 Elmwood Avenue, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Xiao-Qun
authors.initials: XQ
authors.lastname: Wang
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nigro
authors.forename: Cameron
authors.initials: C
authors.lastname: World
authors.forename: Keigi
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D036904:Leukocyte Rolling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D002352:Carrier Proteins; C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; C486715:TXNIP protein, human; D014409:Tumor Necrosis Factor-alpha; C445672:Txnip protein, mouse; D019010:Vascular Cell Adhesion Molecule-1; D013879:Thioredoxins