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(Circulation. 2004;110:337-343.)
© 2004 American Heart Association, Inc.

Original Articles

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; 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.

Correspondence to Professor M.M. Thompson, Department of Vascular Surgery, St. George’s Hospital Medical School, 4th Floor, St James Wing, St. George’s Hospital NHS Trust, Blackshaw Rd, London SW17 0QT UK. E-mail m.thompson{at}sghms.ac.uk

Received July 15, 2003; de novo received December 11, 2003; revision received March 10, 2004; accepted March 22, 2004.

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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