Published Online
on May 15, 2006

A more recent version of this article appeared on May 23, 2006

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Submitted on September 8, 2005
Revised on February 23, 2006
Accepted on March 10, 2006

Suppression of Atherosclerotic Plaque Progression and Instability by Tissue Inhibitor of Metalloproteinase-2. Involvement of Macrophage Migration and Apoptosis

Jason L. Johnson PhD^*, Andrew H. Baker PhD, Kazuhiro Oka PhD, Lawrence Chan MBBS, DSc, Andrew C. Newby PhD, Christopher L. Jackson PhD, and Sarah J. George PhD

From the Bristol Heart Institute (J.L.J., A.C.N., C.L.J., S.J.G.), University of Bristol, Bristol, England; the British Heart Foundation Glasgow Cardiovascular Research Centre (A.H.B.), Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland; and the Departments of Medicine and Molecular and Cellular Biology (K.O., L.C.), Baylor College of Medicine, Houston, Tex.

^* To whom correspondence should be addressed. E-mail: jason.l.johnson{at}bristol.ac.uk.

Background--Matrix metalloproteinase (MMP)-associated extracellular matrix degradation is thought to contribute to the progression and rupture of atherosclerotic plaques. However, direct evidence of this concept remains elusive. We hypothesized that overexpression of tissue inhibitor of metalloproteinase (TIMP)-1 or TIMP-2 would attenuate atherosclerotic plaque development and instability in high fat-fed apolipoprotein E-knockout (apoE^-/-) mice.

Methods and Results--Seventy male apoE^-/- mice (n=10/group) fed a high-fat diet for 7 weeks were injected intravenously with first-generation adenoviruses expressing the gene for human TIMP-1 (RAdTIMP-1) or TIMP-2 (RAdTIMP-2) or a control adenovirus (RAd66) and were fed a high-fat diet for a further 4 weeks. Analysis of brachiocephalic artery plaques revealed that RAdTIMP-2 but not RAdTIMP-1 infection resulted in a marked reduction (48±13%, P<0.05) in lesion area compared with that in control animals. Markers associated with plaque instability, assessed by smooth muscle cell and macrophage content and the presence of buried fibrous caps, were significantly reduced by RAdTIMP-2. Effects on lesion size were not sustained with first-generation adenoviruses, but murine TIMP-2 overexpression mediated by helper-dependent adenoviral vectors exerted significant effects on plaques assessed 11 weeks after infection. In an attempt to determine the mechanism of action, we treated macrophages and macrophage-derived foam cells with exogenous TIMP-2 in vitro. TIMP-2 significantly inhibited migration and apoptosis of macrophages and foam cells, whereas TIMP-1 failed to exert similar effects.

Conclusions--Overexpression of TIMP-2 but not TIMP-1 inhibits atherosclerotic plaque development and destabilisation, possibly through modulation of macrophage and foam cell behavior. Helper-dependent adenovirus technology is required for these effects to be maintained long term.

Key words: adenovirus • atherosclerosis • gene therapy • metalloproteinases • plaque

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