on November 23, 2005
Published online before print November 23, 2005, doi: 10.1161/01.ATV.0000197795.56960.64
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Submitted on May 2, 2005
Accepted on November 3, 2005
Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis
R. de Nooijer *;
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
* To whom correspondence should be addressed. 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.
Key words: adenovirus • atherosclerosis • metalloproteinases • remodeling • vulnerable plaque
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