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
and Gomez, Maria
LU
(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:
https://lup.lub.lu.se/record/415256
- author
- Öhman, Jenny
LU
; Berglund, Lisa
LU
; Chen, YW
; Molkentin, JD
; Erlinge, David
LU
and Gomez, Maria
LU
- organization
- publishing date
- 2006
- 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
- 2024-02-23 00:03:25
@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}},
keywords = {{extracellular nucleotides; high glucose; vascular smooth muscle; GSK-3; NFAT}},
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}},
}