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TIMP3 is Reduced in Atherosclerotic Plaques from Subjects with Type 2 Diabetes and Increased by SirT1

Overview

Overview

Journal Diabetes

Specialty Endocrinology

Date 2009 Jul 8

PMID 19581416

Citations 69

Authors

Authors

Marina Cardellini

Rossella Menghini

Eugenio Martelli

Viviana Casagrande

Arianna Marino

Stefano Rizza

Ottavia Porzio

Alessandro Mauriello

Anna Solini

Arnaldo Ippoliti

Renato Lauro

Franco Folli

Massimo Federici

Affiliations

Affiliations

Soon will be listed here.

Abstract

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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