title: A novel transcriptional mechanism of cell type-specific regulation of vascular gene expression by glucose.
abstract: OBJECTIVE
  Vascular diabetic complications are associated with abnormal extracellular matrix and dysfunction of vascular cells, which later result in aberrant angiogenesis and development of atherosclerotic lesions. The tissue and cell specificity of the effects of high glucose are well recognized, but the underlying cell type-specific molecular mechanisms controlled by glucose are still unclear. We sought to identify cell type-specific mechanisms by which high glucose regulates transcription of genes in vascular cells.
  
  
  RESULTS
  Thrombospondin-1 is a potent antiangiogenic protein associated with development of several diabetic complications and regulated by high glucose in multiple cell types. We report that distinct cell type-specific mechanisms regulate thrombospondin-1 gene (THBS1) transcription in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in response to high glucose: although a proximal fragment of 280 nucleotides is sufficient to drive transcription in ECs, THBS1 was regulated cooperatively by interaction between proximal (-272 to -275) and distal (-1016 to -1019) promoter elements in VSMCs. Transcription factors activated by high glucose in VSMCs were cell type-specific. The formation of a single complex interacting with both distal and proximal glucose-responsive elements of THBS1 promoter in VSMCs was confirmed using gel-shift assays, binding sequence decoy oligomers, and specific mutant promoter fragments.
  
  
  CONCLUSIONS
  Transcriptional response of vascular cells to high glucose is cell type-specific and involves activation of distinct transcription factors, providing a basis for tissue-specific changes of vasculature in diabetics.
authors.affiliation: Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Raman
authors.forename: Christy
authors.initials: C
authors.lastname: Harry
authors.forename: Malory
authors.initials: M
authors.lastname: Weber
authors.forename: Irene
authors.initials: I
authors.lastname: Krukovets
authors.forename: Olga I
authors.initials: OI
authors.lastname: Stenina
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003925:Diabetic Angiopathies / Q000235:genetics* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D019700:Thrombospondin 1 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
chemical_list: D018336:Receptors, Aryl Hydrocarbon; D019700:Thrombospondin 1; D014157:Transcription Factors; D005947:Glucose