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- Title
TIMP3 Is Reduced in Atherosclerotic Plaques From Subjects With Type 2 Diabetes and Increased by SirT1.
- Authors
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
- 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 ADAMIO, 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. SifT1 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 SifT1 levels. In smooth muscle cells, inhibition of SirT1 activity and levels reduced TIMP3 expression, whereas SifT1 overexpression increased TIMP3 promoter activity. CONCLUSIONS--In atherosclerotic plaques from subjects with type 2 diabetes, the deregulation of ADAM 17 and MMP9 activities is related to inadequate expression of TIMP3 via SirT1. Studies in vascular cells confirmed the role of SifT1 in tuning TIMP3 expression. Diabetes 58:2396-2401, 2009
- Subjects
METALLOPROTEINASES; ATHEROSCLEROTIC plaque; PEOPLE with diabetes; ATHEROSCLEROSIS; INSULIN resistance; VASCULAR smooth muscle; MUSCLE cells; SMALL interfering RNA
- Publication
Diabetes, 2009, Vol 58, Issue 10, p2396
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db09-0280