TIMP3 is reduced in atherosclerotic plaques from subjects with type 2 diabetes and increased by SirT1
- Marina Cardellini, MD*,
- Rossella Menghini, PhD*,
- Eugenio Martelli, MD†,
- Viviana Casagrande, BS*,
- Arianna Marino, BS*,
- Stefano Rizza, MD/PhD*,
- Ottavia Porzio, MD*,
- Alessandro Mauriello, MD‡,
- Anna Solini, MD§,
- Arnaldo Ippoliti, MD†,
- Renato Lauro, MD*,
- Franco Folli, MD¶ and
- Massimo Federici, MD (federicm{at}uniroma2.it)*
- From Departments of *Internal Medicine
- †Surgery
- ‡Biopathology and Diagnostic Imaging, University of Rome “Tor Vergata”, Rome, Italy
- §Department of Internal Medicine, University of Pisa
- ¶Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas
Abstract
Objective: Atherosclerosis is accelerated in patients with Type 2 Diabetes Mellitus (DM2) 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 MetalloProteinase (MMP), as a gene modifier for insulin resistance and vascular inflammation in mice. Here we tested its association with atherosclerosis in patients with type 2 diabetes mellitus (DM2) and identified Sirtuin 1 (SirT1) as a major regulator of TIMP3 expression.
Research design and methods: We investigated ADAM10/17/MMP9, TIMP1/2/3/4 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 (siRNA), 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 DM2 leading to ADAM17 and MMP9 overactivity. Reduced expression of TIMP3 was associated in vivo to SirT1 levels. In smooth muscle cells, inhibition of SirT1 activity and levels reduced TIMP3 expression, while 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.
Footnotes
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- Received February 24, 2009.
- Accepted June 23, 2009.
- Copyright © American Diabetes Association
