Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1523873
- author
- organization
-
- EXODIAB: Excellence of Diabetes Research in Sweden
- Cardiovascular Research - Immunity and Atherosclerosis (research group)
- Stem Cell Center
- Department of Clinical Sciences, Malmö
- Islet cell physiology (research group)
- Vessel Wall Biology (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- EpiHealth: Epidemiology for Health
- publishing date
- 2010
- 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}}, }