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TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1

OBJECTIVE: Atherosclerosis is accelerated in subjects with type 2 diabetes by unknown mechanisms. We identified tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of A disintegrin and metalloprotease domain 17 (ADAM17) and other matrix metalloproteinases (MMPs), as a gene modi...

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Autores principales: Cardellini, Marina, Menghini, Rossella, Martelli, Eugenio, Casagrande, Viviana, Marino, Arianna, Rizza, Stefano, Porzio, Ottavia, Mauriello, Alessandro, Solini, Anna, Ippoliti, Arnaldo, Lauro, Renato, Folli, Franco, Federici, Massimo
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750223/
https://www.ncbi.nlm.nih.gov/pubmed/19581416
http://dx.doi.org/10.2337/db09-0280
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author Cardellini, Marina
Menghini, Rossella
Martelli, Eugenio
Casagrande, Viviana
Marino, Arianna
Rizza, Stefano
Porzio, Ottavia
Mauriello, Alessandro
Solini, Anna
Ippoliti, Arnaldo
Lauro, Renato
Folli, Franco
Federici, Massimo
author_facet Cardellini, Marina
Menghini, Rossella
Martelli, Eugenio
Casagrande, Viviana
Marino, Arianna
Rizza, Stefano
Porzio, Ottavia
Mauriello, Alessandro
Solini, Anna
Ippoliti, Arnaldo
Lauro, Renato
Folli, Franco
Federici, Massimo
author_sort Cardellini, Marina
collection PubMed
description OBJECTIVE: Atherosclerosis is accelerated in subjects with type 2 diabetes by unknown mechanisms. We identified tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of A disintegrin and metalloprotease domain 17 (ADAM17) and other matrix metalloproteinases (MMPs), as a gene modifier for insulin resistance and vascular inflammation in mice. We tested its association with atherosclerosis in subjects with type 2 diabetes and identified Sirtuin 1 (SirT1) as a major regulator of TIMP3 expression. RESEARCH DESIGN AND METHODS: We investigated ADAM10, ADAM17, MMP9, TIMP1, TIMP2, TIMP3, and TIMP4 expression levels in human carotid atherosclerotic plaques (n = 60) from subjects with and without diabetes. Human vascular smooth muscle cells exposed to several metabolic stimuli were used to identify regulators of TIMP3 expression. SirT1 small interference RNA, cDNA, and TIMP3 promoter gene reporter were used to study SirT1-dependent regulation of TIMP3. RESULTS: Here, we show that in human carotid atherosclerotic plaques, TIMP3 was significantly reduced in subjects with type 2 diabetes, leading to ADAM17 and MMP9 overactivity. Reduced expression of TIMP3 was associated in vivo with SirT1 levels. In smooth muscle cells, inhibition of SirT1 activity and levels reduced TIMP3 expression, whereas SirT1 overexpression increased TIMP3 promoter activity. CONCLUSIONS: In atherosclerotic plaques from subjects with type 2 diabetes, the deregulation of ADAM17 and MMP9 activities is related to inadequate expression of TIMP3 via SirT1. Studies in vascular cells confirmed the role of SirT1 in tuning TIMP3 expression.
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spelling pubmed-27502232010-10-01 TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1 Cardellini, Marina Menghini, Rossella Martelli, Eugenio Casagrande, Viviana Marino, Arianna Rizza, Stefano Porzio, Ottavia Mauriello, Alessandro Solini, Anna Ippoliti, Arnaldo Lauro, Renato Folli, Franco Federici, Massimo Diabetes Original Article OBJECTIVE: Atherosclerosis is accelerated in subjects with type 2 diabetes by unknown mechanisms. We identified tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of A disintegrin and metalloprotease domain 17 (ADAM17) and other matrix metalloproteinases (MMPs), as a gene modifier for insulin resistance and vascular inflammation in mice. We tested its association with atherosclerosis in subjects with type 2 diabetes and identified Sirtuin 1 (SirT1) as a major regulator of TIMP3 expression. RESEARCH DESIGN AND METHODS: We investigated ADAM10, ADAM17, MMP9, TIMP1, TIMP2, TIMP3, and TIMP4 expression levels in human carotid atherosclerotic plaques (n = 60) from subjects with and without diabetes. Human vascular smooth muscle cells exposed to several metabolic stimuli were used to identify regulators of TIMP3 expression. SirT1 small interference RNA, cDNA, and TIMP3 promoter gene reporter were used to study SirT1-dependent regulation of TIMP3. RESULTS: Here, we show that in human carotid atherosclerotic plaques, TIMP3 was significantly reduced in subjects with type 2 diabetes, leading to ADAM17 and MMP9 overactivity. Reduced expression of TIMP3 was associated in vivo with SirT1 levels. In smooth muscle cells, inhibition of SirT1 activity and levels reduced TIMP3 expression, whereas SirT1 overexpression increased TIMP3 promoter activity. CONCLUSIONS: In atherosclerotic plaques from subjects with type 2 diabetes, the deregulation of ADAM17 and MMP9 activities is related to inadequate expression of TIMP3 via SirT1. Studies in vascular cells confirmed the role of SirT1 in tuning TIMP3 expression. American Diabetes Association 2009-10 2009-07-06 /pmc/articles/PMC2750223/ /pubmed/19581416 http://dx.doi.org/10.2337/db09-0280 Text en © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Article
Cardellini, Marina
Menghini, Rossella
Martelli, Eugenio
Casagrande, Viviana
Marino, Arianna
Rizza, Stefano
Porzio, Ottavia
Mauriello, Alessandro
Solini, Anna
Ippoliti, Arnaldo
Lauro, Renato
Folli, Franco
Federici, Massimo
TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1
title TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1
title_full TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1
title_fullStr TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1
title_full_unstemmed TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1
title_short TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1
title_sort timp3 is reduced in atherosclerotic plaques from subjects with type 2 diabetes and increased by sirt1
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750223/
https://www.ncbi.nlm.nih.gov/pubmed/19581416
http://dx.doi.org/10.2337/db09-0280
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