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Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia.

Berglund, Lisa LU ; Zetterqvist, Anna LU orcid ; Öhman, Jenny LU ; Sigvardsson, Mikael LU ; González Bosc, Laura V ; Smith, Maj-Lis LU ; Salehi, S Albert LU orcid ; Agardh, Elisabet LU ; Nordin Fredrikson, Gunilla LU and Agardh, Carl-David LU , et al. (2010) In Arteriosclerosis, Thrombosis and Vascular Biology 30. p.154-218
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arteriosclerosis, Thrombosis and Vascular Biology
volume
30
pages
154 - 218
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000273799900017
  • pmid:19965778
  • scopus:75149179578
  • pmid:19965778
ISSN
1524-4636
DOI
10.1161/ATVBAHA.109.199299
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Department of Clinical Sciences, Malmö (013240000), Experimental Cardiovascular Research Unit (013242110), Stem Cell Center (013041110), Vessel Wall Biology (013212028), Islet cell physiology (013212142), Unit on Vascular Diabetic Complications (013241510)
id
49f8a4b8-ccc8-48b1-a019-f7c6bbbcd476 (old id 1523873)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19965778?dopt=Abstract
date added to LUP
2016-04-04 08:55:24
date last changed
2022-08-15 21:45:53
@article{49f8a4b8-ccc8-48b1-a019-f7c6bbbcd476,
  abstract     = {{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.}},
  author       = {{Berglund, Lisa and Zetterqvist, Anna and Öhman, Jenny and Sigvardsson, Mikael and González Bosc, Laura V and Smith, Maj-Lis and Salehi, S Albert and Agardh, Elisabet and Nordin Fredrikson, Gunilla and Agardh, Carl-David and Nilsson, Jan and Wamhoff, Brian R and Hultgårdh, Anna and Gomez, Maria}},
  issn         = {{1524-4636}},
  language     = {{eng}},
  pages        = {{154--218}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Arteriosclerosis, Thrombosis and Vascular Biology}},
  title        = {{Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia.}},
  url          = {{http://dx.doi.org/10.1161/ATVBAHA.109.199299}},
  doi          = {{10.1161/ATVBAHA.109.199299}},
  volume       = {{30}},
  year         = {{2010}},
}