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Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia.

Author:
  • Lisa Berglund
  • Anna Zetterqvist
  • Jenny Öhman
  • Mikael Sigvardsson
  • Laura V González Bosc
  • Maj-Lis Smith
  • S Albert Salehi
  • Elisabet Agardh
  • Gunilla Nordin Fredrikson
  • Carl-David Agardh
  • Jan Nilsson
  • Brian R Wamhoff
  • Anna Hultgårdh
  • Maria Gomez
Publishing year: 2010
Language: English
Pages: 154-218
Publication/Series: Arteriosclerosis, Thrombosis and Vascular Biology
Volume: 30
Document type: Journal article
Publisher: Lippincott Williams Wilkins Hagerstown, MD
Additional info: The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Department of Clinical Sciences, Malmö (013240000), Experimental Cardiovascular Research Unit (013242110), Stem Cell Center (013041110), Vessel Wall Biology (013212028), Islet cell physiology (013212142), Unit on Vascular Diabetic Complications (013241510)

Abstract english

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. METHODS AND 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.

Keywords

  • Cardiac and Cardiovascular Systems

Other

Published
  • Cardiovascular Research - Immunity and Atherosclerosis
  • Islet cell physiology
  • Vessel Wall Biology
  • ISSN: 1524-4636
E-mail: jan [dot] nilsson [at] med [dot] lu [dot] se

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00