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Maria Gomez

Maria Gomez

Professor

Maria Gomez

High glucose activates nuclear factor of activated T cells in native vascular smooth muscle

Author

  • Jenny Öhman
  • Lisa Berglund
  • YW Chen
  • JD Molkentin
  • David Erlinge
  • Maria Gomez

Summary, in English

Objective-Hyperglycemia has been suggested to play a role in the development of vascular disease associated with diabetes. Atypical Ca2+ signaling and gene expression are characteristic of vascular dysfunction; however, little is known regarding the effects of high glucose on Ca2+-dependent transcription in the vascular wall. Methods and Results-Using confocal immunofluorescence, we show that modest elevation of extracellular glucose (ie, from 2 to 11.5 mmol/L) increased [Ca2+](i), leading to nuclear accumulation of nuclear factor of activated T cells (NFAT) in intact cerebral arteries from mouse. This was accompanied by increased NFAT-dependent transcriptional activity. Both the increase in Ca2+ and NFAT activation were prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. We provide evidence that the potent vasoconstrictors and growth stimulators UTP and UDP mediate glucose-induced NFAT activation via P2Y receptors. NFAT nuclear accumulation was inhibited by the voltage-dependent Ca2+ channel blockers verapamil and nifedipine, the calcineurin inhibitor cyclosporine A, and the novel NFAT blocker A-285222. High glucose also regulated glycogen synthase kinase 3 beta and c-Jun N-terminal kinase activity, yielding decreased kinase activity and reduced export of NFAT from the nucleus, providing additional mechanisms underlying the glucose-induced NFAT activation. Conclusions-Our results identify the calcineurin/NFAT signaling pathway as a potential metabolic sensor for the arterial smooth muscle response to high glucose.

Department/s

  • Cardiology
  • Vascular Physiology

Publishing year

2006

Language

English

Pages

794-800

Publication/Series

Arteriosclerosis, Thrombosis and Vascular Biology

Volume

26

Issue

4

Document type

Journal article

Publisher

Lippincott Williams & Wilkins

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • extracellular nucleotides
  • high glucose
  • vascular smooth muscle
  • GSK-3
  • NFAT

Status

Published

Research group

  • Vascular Physiology

ISBN/ISSN/Other

  • ISSN: 1524-4636