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Jan Nilsson

Professor

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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

Summary, in 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.

Department/s

  • EXODIAB: Excellence in Diabetes Research in Sweden
  • Cardiovascular Research - Immunity and Atherosclerosis
  • Stem Cell Center
  • Department of Clinical Sciences, Malmö
  • Islet cell physiology
  • Vessel Wall Biology
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • EpiHealth: Epidemiology for Health

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

Topic

  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Cardiovascular Research - Immunity and Atherosclerosis
  • Islet cell physiology
  • Vessel Wall Biology

ISBN/ISSN/Other

  • ISSN: 1524-4636