Published Online
on June 28, 2004

A more recent version of this article appeared on July 20, 2004

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Submitted on July 15, 2003
Revised on March 10, 2004
Accepted on March 22, 2004

Unstable Carotid Plaques Exhibit Raised Matrix Metalloproteinase-8 Activity

K. J. Molloy MRCS, M. M. Thompson MD, FRCS^*, J. L. Jones PhD, FRCPath, E. C. Schwalbe BSc, P. R.F. Bell MD, FRCS, A. R. Naylor MD, FRCS, and I. M. Loftus MD, FRCS

From the Departments of Surgery (K.J.M., E.C.S., P.R.F.B., A.R.N., I.M.L.) and Histopathology (J.L.J.), University of Leicester, and Department of Vascular Surgery and Cardiovascular Research Group, St George’s Hospital Medical School, London (M.M.T.), UK.

^* To whom correspondence should be addressed. E-mail: m.thompson{at}sghms.ac.uk.

Background--The fibrous cap of atherosclerotic plaques is composed predominantly of type I and III collagen. Unstable carotid plaques are characterized by rupture of their cap, leading to thromboembolism and stroke. The proteolytic mechanisms causing plaque disruption are undefined, but the collagenolytic matrix metalloproteinase (MMP) -1, -8, and -13 may be implicated. The aim of this study was to quantify the concentrations of these collagenases in carotid plaques and to determine their relationship to markers of plaque instability.

Methods and Results--Atherosclerotic plaques were collected from 159 patients undergoing carotid endarterectomy. The presence and timing of carotid territory symptoms were ascertained. Preoperative embolization was recorded by transcranial Doppler. Each plaque was assessed for histological features of instability. Plaque MMP concentrations were quantified with ELISA. Significantly higher concentrations of active MMP-8 were observed in the plaques of symptomatic patients (20.5 versus 11.4 ng/g; P=0.0002), in plaques of emboli-positive patients (22.7 versus 13.5 ng/g; P=0.0037), and in those plaques showing histological evidence of rupture (20.8 versus 14.7 ng/g; P=0.0036). No differences were seen in the levels of MMP-1 and MMP-13. Immunohistochemistry, in situ hybridization, and colocalization studies confirmed the presence of MMP-8 protein and mRNA within the plaque, which colocalized with macrophages.

Conclusions--These data suggest that the active form of MMP-8 may be partly responsible for degradation of the collagen cap of atherosclerotic plaques. This enzyme represents an attractive target for drug therapy aimed at stabilizing vulnerable plaques.

Key words: atherosclerosis • carotid arteries • collagen • metalloproteinases • plaque

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