Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice
Objective of the Study: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed...
Saved in:
| Main Author: | |
|---|---|
| Other Authors: | , , , , , , , , |
| Format: | article |
| Language: | English |
| Published: |
2013
|
| Online Access: | https://hdl.handle.net/20.500.12008/21978 |
| Tags: |
No Tags, Be the first to tag this record!
|
| _version_ | 1868890211457433600 |
|---|---|
| author | Zetterqvist, Anna V. |
| author2 | Berglund, Lisa M. Blanco, Fabiana Garcia-Vaz, Eliana Wigren, Maria Duner, Pontus Dutius Andersson, Anna-Maria Nilsson, Jan Bengtsson, Eva Spegel, Peter |
| author2_role | author author author author author author author author author |
| author_browse | Bengtsson, Eva Berglund, Lisa M. Blanco, Fabiana Duner, Pontus Dutius Andersson, Anna-Maria Garcia-Vaz, Eliana Nilsson, Jan Spegel, Peter Wigren, Maria Zetterqvist, Anna V. |
| author_facet | Zetterqvist, Anna V. Berglund, Lisa M. Blanco, Fabiana Garcia-Vaz, Eliana Wigren, Maria Duner, Pontus Dutius Andersson, Anna-Maria Nilsson, Jan Bengtsson, Eva Spegel, Peter |
| author_role | author |
| collection | COLIBRI |
| dc.contributor.none.fl_str_mv | Zetterqvist Anna V. Berglund Lisa M. Blanco Fabiana Garcia-Vaz Eliana Wigren Maria Duner Pontus Dutius Andersson Anna-Maria Nilsson Jan Bengtsson Eva Spegel Peter |
| dc.creator.none.fl_str_mv | Zetterqvist, Anna V. Berglund, Lisa M. Blanco, Fabiana Garcia-Vaz, Eliana Wigren, Maria Duner, Pontus Dutius Andersson, Anna-Maria Nilsson, Jan Bengtsson, Eva Spegel, Peter |
| dc.date.none.fl_str_mv | 2013 2019-09-27T17:50:07Z 2019-09-27T17:50:07Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | Zetterqvist, A, Berglund, L, Blanco, F, y otros. "Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice". PLoS ONE Vol.8, no.6 [en línea] 2013, doi:10.1371/journal.pone.0065020 https://hdl.handle.net/20.500.12008/21978 |
| dc.language.none.fl_str_mv | en eng |
| dc.publisher.none.fl_str_mv | PLOS ONE Editorial Board |
| dc.relation.none.fl_str_mv | PLoS ONE Vol.8, no.6, 2013 |
| dc.rights.none.fl_str_mv | info:eu-repo/semantics/openAccess Licencia Creative Commons Atribución (CC - BY) |
| dc.source.none.fl_str_mv | reponame:COLIBRI instname:Universidad de la República instacron:Universidad de la República |
| dc.title.none.fl_str_mv | Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice |
| dc.type.none.fl_str_mv | Artículo info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| description | Objective of the Study: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. Methodology and Principal Findings: Streptozotocin (STZ)-induced diabetes in apolipoprotein E2/2 mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A- 285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. Conclusions: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | anni_debcb8d7aeeaaa9ec9fb8df2e0f349d6 |
| identifier_str_mv | Zetterqvist, A, Berglund, L, Blanco, F, y otros. "Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice". PLoS ONE Vol.8, no.6 [en línea] 2013, doi:10.1371/journal.pone.0065020 |
| instacron_str | Universidad de la República |
| institution | Universidad de la República |
| instname_str | Universidad de la República |
| language | eng |
| language_invalid_str_mv | en |
| network_acronym_str | anni |
| network_name_str | oai-lr-anni |
| oai_identifier_str | oai:colibri.udelar.edu.uy:20.500.12008/21978 |
| publishDate | 2013 |
| publishDateSort | 2013 |
| publisher.none.fl_str_mv | PLOS ONE Editorial Board |
| reponame_str | COLIBRI |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | Licencia Creative Commons Atribución (CC - BY) |
| spelling | Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic MiceZetterqvist, Anna V.Berglund, Lisa M.Blanco, FabianaGarcia-Vaz, ElianaWigren, MariaDuner, PontusDutius Andersson, Anna-MariaNilsson, JanBengtsson, EvaSpegel, PeterObjective of the Study: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. Methodology and Principal Findings: Streptozotocin (STZ)-induced diabetes in apolipoprotein E2/2 mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A- 285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. Conclusions: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications.PLOS ONE Editorial BoardZetterqvist Anna V.Berglund Lisa M.Blanco FabianaGarcia-Vaz ElianaWigren MariaDuner PontusDutius Andersson Anna-MariaNilsson JanBengtsson EvaSpegel Peter2019-09-27T17:50:07Z2019-09-27T17:50:07Z2013Artículoinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfZetterqvist, A, Berglund, L, Blanco, F, y otros. "Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice". PLoS ONE Vol.8, no.6 [en línea] 2013, doi:10.1371/journal.pone.0065020https://hdl.handle.net/20.500.12008/21978reponame:COLIBRIinstname:Universidad de la Repúblicainstacron:Universidad de la RepúblicaenengPLoS ONE Vol.8, no.6, 2013Las obras depositadas en el Repositorio se rigen por la Ordenanza de los Derechos de la Propiedad Intelectual de la Universidad de la República.(Res. Nº 91 de C.D.C. de 8/III/1994 – D.O. 7/IV/1994) y por la Ordenanza del Repositorio Abierto de la Universidad de la República (Res. Nº 16 de C.D.C. de 07/10/2014)info:eu-repo/semantics/openAccessLicencia Creative Commons Atribución (CC - BY)oai:colibri.udelar.edu.uy:20.500.12008/219782026-04-14T10:28:01Z |
| spellingShingle | Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice Zetterqvist, Anna V. |
| status_str | publishedVersion |
| title | Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice |
| title_full | Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice |
| title_fullStr | Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice |
| title_full_unstemmed | Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice |
| title_short | Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice |
| title_sort | Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice |
| url | https://hdl.handle.net/20.500.12008/21978 |