title: Nuclear factor of activated T cells regulates osteopontin expression in arterial smooth muscle in response to diabetes-induced hyperglycemia.
abstract: OBJECTIVE
  Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca(2+)/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications.
  
  
  RESULTS
  An intraperitoneal glucose-tolerance test in mice increased NFATc3 nuclear accumulation in vascular smooth muscle. Streptozotocin-induced diabetes resulted in increased NFATc3 transcriptional activity in arteries of NFAT-luciferase transgenic mice. Two NFAT-responsive sequences in the osteopontin (OPN) promoter were identified. This proinflammatory cytokine has been shown to exacerbate atherosclerosis and restenosis. Activation of NFAT resulted in increased OPN mRNA and protein in native arteries. Glucose-induced OPN expression was prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. The calcineurin inhibitor cyclosporin A or the novel NFAT blocker A-285222 prevented glucose-induced OPN expression. Furthermore, diabetes resulted in higher OPN expression, which was significantly decreased by in vivo treatment with A-285222 for 4 weeks or prevented in arteries from NFATc3(-/-) mice.
  
  
  CONCLUSIONS
  These results identify a glucose-sensitive transcription pathway in vivo, revealing a novel molecular mechanism that may underlie vascular complications of diabetes.
authors: Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden.
authors: Lisa M
authors: LM
authors: Nilsson-Berglund
authors: Anna V
authors: AV
authors: Zetterqvist
authors: Jenny
authors: J
authors: Nilsson-Ohman
authors: Mikael
authors: M
authors: Sigvardsson
authors: Laura V
authors: LV
authors: González Bosc
authors: Maj-Lis
authors: ML
authors: Smith
authors: Albert
authors: A
authors: Salehi
authors: Elisabet
authors: E
authors: Agardh
authors: Gunilla Nordin
authors: GN
authors: Fredrikson
authors: Carl-David
authors: CD
authors: Agardh
authors: Jan
authors: J
authors: Nilsson
authors: Brian R
authors: BR
authors: Wamhoff
authors: Anna
authors: A
authors: Hultgårdh-Nilsson
authors: Maria F
authors: MF
authors: Gomez
mesh_terms: D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D001158:Arteries / Q000378:metabolism; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014544:Uridine Triphosphate / Q000378:metabolism
chemical_list: C494244:A 285222; D001786:Blood Glucose; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D011720:Pyrazoles; D012333:RNA, Messenger; C506896:Spp1 protein, mouse; D053495:Osteopontin; D016572:Cyclosporine; D019703:Calcineurin; D001081:Apyrase; D014544:Uridine Triphosphate