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

Research output: Contribution to journalArticle

Abstract

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.

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Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems

Keywords

  • extracellular nucleotides, high glucose, vascular smooth muscle, GSK-3, NFAT
Original languageEnglish
Pages (from-to)794-800
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume26
Issue number4
Publication statusPublished - 2006
Publication categoryResearch
Peer-reviewedYes

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