Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy.
OBJECTIVE
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.
Fujimoto
Shinichiro
S
University of California, Irvine School of Medicine, Irvine, California.
Hartung
Dagmar
D
University of California, Irvine School of Medicine, Irvine, California.
Ohshima
Satoru
S
University of California, Irvine School of Medicine, Irvine, California.
Edwards
D Scott
DS
Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts.
Zhou
Jun
J
University of California, Irvine School of Medicine, Irvine, California.
Yalamanchili
Padmaja
P
Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts.
Azure
Michael
M
Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts.
Fujimoto
Ai
A
University of California, Irvine School of Medicine, Irvine, California.
Isobe
Satoshi
S
University of California, Irvine School of Medicine, Irvine, California.
Matsumoto
Yuji
Y
University of California, Irvine School of Medicine, Irvine, California.
Boersma
Hendricus
H
University Medical Center, Groningen, the Netherlands.
Wong
Nathan
N
University of California, Irvine School of Medicine, Irvine, California.
Yamazaki
Junichi
J
Toho University School of Medicine, Ohmori Hospital, Tokyo, Japan.
Narula
Navneet
N
University of California, Irvine School of Medicine, Irvine, California.
Petrov
Artiom
A
University of California, Irvine School of Medicine, Irvine, California. Electronic address: adpetrov@uci.edu.
Narula
Jagat
J
University of California, Irvine School of Medicine, Irvine, California.
D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D050197:Atherosclerosis / Q000178:diet therapy* / Q000188:drug therapy* / Q000473:pathology; D003131:Combined Modality Therapy; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008956:Models, Chemical; D011817:Rabbits; D013667:Technetium / Q000494:pharmacology; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D013667:Technetium; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9