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

Öhman, Jenny LU ; Berglund, Lisa LU ; Chen, YW ; Molkentin, JD ; Erlinge, David LU orcid and Gomez, Maria LU orcid (2006) In Arteriosclerosis, Thrombosis and Vascular Biology 26(4). p.794-800
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
extracellular nucleotides, high glucose, vascular smooth muscle, GSK-3, NFAT
in
Arteriosclerosis, Thrombosis and Vascular Biology
volume
26
issue
4
pages
794 - 800
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000236223200018
  • pmid:16469950
  • scopus:33646679107
ISSN
1524-4636
DOI
10.1161/01.ATV.0000209513.00765.13
language
English
LU publication?
yes
id
fe974a0b-335d-430c-aafc-992fd894f497 (old id 415256)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16469950&dopt=Abstract
date added to LUP
2016-04-01 11:39:04
date last changed
2021-08-04 01:17:51
@article{fe974a0b-335d-430c-aafc-992fd894f497,
  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.},
  author       = {Öhman, Jenny and Berglund, Lisa and Chen, YW and Molkentin, JD and Erlinge, David and Gomez, Maria},
  issn         = {1524-4636},
  language     = {eng},
  number       = {4},
  pages        = {794--800},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Arteriosclerosis, Thrombosis and Vascular Biology},
  title        = {High glucose activates nuclear factor of activated T cells in native vascular smooth muscle},
  url          = {http://dx.doi.org/10.1161/01.ATV.0000209513.00765.13},
  doi          = {10.1161/01.ATV.0000209513.00765.13},
  volume       = {26},
  year         = {2006},
}