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J Am Coll Cardiol. 2008 Dec 2;52(23):1847-1857. doi: 10.1016/j.jacc.2008.08.048.

Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy.

Author information

1
University of California, Irvine School of Medicine, Irvine, California.
2
Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts.
3
University Medical Center, Groningen, the Netherlands.
4
Toho University School of Medicine, Ohmori Hospital, Tokyo, Japan.
5
University of California, Irvine School of Medicine, Irvine, California. Electronic address: adpetrov@uci.edu.

Abstract

OBJECTIVES:

This study sought to evaluate the feasibility of noninvasive detection of matrix metalloproteinase (MMP) activity in experimental atherosclerosis using technetium-99m-labeled broad matrix metalloproteinase inhibitor (MPI) and to determine the effect of dietary modification and statin treatment on MMP activity.

BACKGROUND:

The MMP activity in atherosclerotic lesions contributes to the vulnerability of atherosclerotic plaques to rupture.

METHODS:

Atherosclerosis was produced in 34 New Zealand White rabbits by balloon de-endotheliazation of the abdominal aorta and a high-cholesterol diet. In addition, 12 unmanipulated rabbits were used as controls and 3 for blood clearance characteristics. In vivo micro-single-photon emission computed tomography (SPECT) imaging was performed after radiolabeled MPI administration. Subsequently, aortas were explanted to quantitatively measure percent injected dose per gram (%ID/g) MPI uptake. Histological and immunohistochemical characterization was performed and the extent of MMP activity was determined by gel zymography or enzyme-linked immunosorbent assays.

RESULTS:

The MPI uptake in atherosclerotic lesions (n = 18) was clearly visualized by micro-SPECT imaging; MPI uptake was markedly reduced by administration of unlabeled MPI before the radiotracer (n = 4). The MPI uptake was also significantly reduced after diet withdrawal (n = 6) and fluvastatin treatment (n = 6); no uptake was observed in normal control rabbits (n = 12). The %ID/g MPI uptake (0.10 +/- 0.03%) in the atherosclerotic lesions was significantly higher than the uptake in control aorta (0.016 +/- 0.004%, p < 0.0001). Uptake in fluvastatin (0.056 +/- 0.011%, p < 0.0005) and diet withdrawal groups (0.043 +/- 0.011%, p < 0.0001) was lower than the untreated group. The MPI uptake correlated with immunohistochemically verified macrophage infiltration (r = 0.643, p < 0.0001), and MMP-2 (r = 0.542, p < 0.0001) or MMP-9 (r = 0.578, p < 0.0001) expression in plaques.

CONCLUSIONS:

The present data show the feasibility of noninvasive detection of MMP activity in atherosclerotic plaques, and confirm that dietary modification and statin therapy reduce MMP activity.

PMID:
19038682
DOI:
10.1016/j.jacc.2008.08.048
[Indexed for MEDLINE]
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