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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:340.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis

R. de Nooijer; C.J.N. Verkleij; J.H. von der Thüsen; J.W. Jukema; E.E. van der Wall; Th. J.C. van Berkel; A.H. Baker; E.A.L. Biessen

From the Division of Biopharmaceutics (R.d.N., C.J.N.V., J.H.v.d.T., Th.J.C.,v.B., E.A.L.B.), Leiden University, Leiden, the Netherlands; Department of Cardiology (R.d.N., J.W.J., E.E.v.d.W.), Leiden University Medical Center, Leiden, the Netherlands; Department of Pathology (J.H.v.d.T.), Leiden University Medical Center, Leiden, the Netherlands; Glasgow Cardiovascular Research Center (A.H.B.), Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

Correspondence to R. de Nooijer, LACDR, Division of Biopharmaceutics, Gorlaeus Laboratory, Einsteinweg 55, 2333 CC Leiden, PO Box 9502, 2300 RA Leiden, the Netherlands. E-mail r.de.nooijer{at}chem.leidenuniv.nl

Background— Matrix metalloproteinase-9 (MMP-9) is involved in atherosclerosis and elevated MMP-9 activity has been found in unstable plaques, suggesting a crucial role in plaque rupture. This study aims to assess the effect of MMP-9 on plaque stability in apolipoprotein E-deficient mice at different stages of plaque progression.

Methods and Results— Atherosclerotic lesions were elicited in carotid arteries by perivascular collar placement. MMP-9 overexpression in intermediate or advanced plaques was effected by intraluminal incubation with an adenovirus (Ad.MMP-9). A subset was coincubated with Ad.TIMP-1. Mock virus served as a control. Plaques were analyzed histologically. In intermediate lesions, MMP-9 overexpression induced outward remodeling, as shown by a 30% increase in media size (p=0.03). In both intermediate and advanced lesions, prevalence of vulnerable plaque morphology tended to be increased. Half of MMP-9–treated lesions displayed intraplaque hemorrhage, whereas in controls and the Ad.MMP-9/Ad.TIMP-1 group this was 8% and 16%, respectively (p=0.007). Colocalization with neovessels may point to neo-angiogenesis as a source for intraplaque hemorrhage.

Conclusion— These data show a differential effect of MMP-9 at various stages of plaque progression and suggest that lesion-targeted MMP-9 inhibition might be a valuable therapeutic modality in stabilizing advanced plaques, but not at earlier stages of lesion progression.

The effect of MMP-9 overexpression at various stages of atherosclerotic lesion development was studied in apoE-deficient mice. In intermediate lesions, MMP-9 results in outward remodeling. In advanced lesions this causes vulnerable plaque morphology accompanied with increased incidence of intraplaque hemorrhage.

Key Words: adenovirus • atherosclerosis • metalloproteinases • remodeling • vulnerable plaque

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