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Sirt1 Inhibits Resistin Expression in Aortic Stenosis

The development of human calcified aortic stenosis (AS) includes age-dependent processes that have been involved in atherosclerosis, such as infiltration of macrophages in aortic valves, which then promote production of many pro-inflammatory cytokines, including resistin. However, the molecular mech...

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Autores principales: Carter, Sophie, Miard, Stéphanie, Roy-Bellavance, Catherine, Boivin, Louise, Li, Zhuo, Pibarot, Philippe, Mathieu, Patrick, Picard, Frédéric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320872/
https://www.ncbi.nlm.nih.gov/pubmed/22493735
http://dx.doi.org/10.1371/journal.pone.0035110
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author Carter, Sophie
Miard, Stéphanie
Roy-Bellavance, Catherine
Boivin, Louise
Li, Zhuo
Pibarot, Philippe
Mathieu, Patrick
Picard, Frédéric
author_facet Carter, Sophie
Miard, Stéphanie
Roy-Bellavance, Catherine
Boivin, Louise
Li, Zhuo
Pibarot, Philippe
Mathieu, Patrick
Picard, Frédéric
author_sort Carter, Sophie
collection PubMed
description The development of human calcified aortic stenosis (AS) includes age-dependent processes that have been involved in atherosclerosis, such as infiltration of macrophages in aortic valves, which then promote production of many pro-inflammatory cytokines, including resistin. However, the molecular mechanisms contributing to these processes are not established. Since Sirt1 has been shown to modulate macrophage biology and inflammation, we examined its levels in human AS and tested its impact on resistin expression. Sirt1 mRNA (p = 0.01) and protein (p<0.05) levels were reduced in explanted valves from AS patients (n = 51) compared to those from control (n = 11) patients. Sirt1 mRNA levels were negatively associated with resistin mRNA levels quantified in AS valves (p = 0.02). Stimulation of Sirt1 by resveratrol or virus-driven overexpression robustly diminished resistin mRNA and protein expression in macrophages, whereas down-regulation of Sirt1 triggered a large increase in resistin expression. These effects were direct, as chromatin immunoprecipitation assays showed that Sirt1 physically interacted with the resistin promoter region at an AP-1 response element. Moreover, Sirt1 blocked c-jun-induced resistin transactivation in gene reporter assays. These findings demonstrate that, in calcified AS, levels of Sirt1 are reduced whereas those of resistin are increased within aortic valve leaflets. Our results also suggest that this loss of Sirt1 expression alleviates its inhibition of resistin transcription in macrophages. Although the overall contribution of this process to the underlying mechanisms for AS disease development remains unresolved, these observations suggest that modification of Sirt1 expression and/or activity could represent a novel approach against inflammation in AS.
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spelling pubmed-33208722012-04-10 Sirt1 Inhibits Resistin Expression in Aortic Stenosis Carter, Sophie Miard, Stéphanie Roy-Bellavance, Catherine Boivin, Louise Li, Zhuo Pibarot, Philippe Mathieu, Patrick Picard, Frédéric PLoS One Research Article The development of human calcified aortic stenosis (AS) includes age-dependent processes that have been involved in atherosclerosis, such as infiltration of macrophages in aortic valves, which then promote production of many pro-inflammatory cytokines, including resistin. However, the molecular mechanisms contributing to these processes are not established. Since Sirt1 has been shown to modulate macrophage biology and inflammation, we examined its levels in human AS and tested its impact on resistin expression. Sirt1 mRNA (p = 0.01) and protein (p<0.05) levels were reduced in explanted valves from AS patients (n = 51) compared to those from control (n = 11) patients. Sirt1 mRNA levels were negatively associated with resistin mRNA levels quantified in AS valves (p = 0.02). Stimulation of Sirt1 by resveratrol or virus-driven overexpression robustly diminished resistin mRNA and protein expression in macrophages, whereas down-regulation of Sirt1 triggered a large increase in resistin expression. These effects were direct, as chromatin immunoprecipitation assays showed that Sirt1 physically interacted with the resistin promoter region at an AP-1 response element. Moreover, Sirt1 blocked c-jun-induced resistin transactivation in gene reporter assays. These findings demonstrate that, in calcified AS, levels of Sirt1 are reduced whereas those of resistin are increased within aortic valve leaflets. Our results also suggest that this loss of Sirt1 expression alleviates its inhibition of resistin transcription in macrophages. Although the overall contribution of this process to the underlying mechanisms for AS disease development remains unresolved, these observations suggest that modification of Sirt1 expression and/or activity could represent a novel approach against inflammation in AS. Public Library of Science 2012-04-06 /pmc/articles/PMC3320872/ /pubmed/22493735 http://dx.doi.org/10.1371/journal.pone.0035110 Text en Carter et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Carter, Sophie
Miard, Stéphanie
Roy-Bellavance, Catherine
Boivin, Louise
Li, Zhuo
Pibarot, Philippe
Mathieu, Patrick
Picard, Frédéric
Sirt1 Inhibits Resistin Expression in Aortic Stenosis
title Sirt1 Inhibits Resistin Expression in Aortic Stenosis
title_full Sirt1 Inhibits Resistin Expression in Aortic Stenosis
title_fullStr Sirt1 Inhibits Resistin Expression in Aortic Stenosis
title_full_unstemmed Sirt1 Inhibits Resistin Expression in Aortic Stenosis
title_short Sirt1 Inhibits Resistin Expression in Aortic Stenosis
title_sort sirt1 inhibits resistin expression in aortic stenosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320872/
https://www.ncbi.nlm.nih.gov/pubmed/22493735
http://dx.doi.org/10.1371/journal.pone.0035110
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