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CLINICAL RESEARCH: CARDIAC IMAGING

Molecular Imaging of Matrix Metalloproteinase in Atherosclerotic Lesions

Resolution With Dietary Modification and Statin Therapy

Shinichiro Fujimoto, MD, PhD^_*, Dagmar Hartung, MD^_*, Satoru Ohshima, MD, PhD^_*, D. Scott Edwards, PhD, Jun Zhou, MD^_*, Padmaja Yalamanchili, PhD, Michael Azure, PhD, Ai Fujimoto, MD, PhD^_*, Satoshi Isobe, MD, PhD^_*, Yuji Matsumoto, MD, PhD^_*, Hendricus Boersma, PharmD, PhD, Nathan Wong, PhD^_*, Junichi Yamazaki, MD, Navneet Narula, MD^_*, Artiom Petrov, PhD^_*,_* and Jagat Narula, MD, PhD, FACC^_*

^_* University of California, Irvine School of Medicine, Irvine, California
Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts
University Medical Center, Groningen, the Netherlands
Toho University School of Medicine, Ohmori Hospital, Tokyo, Japan

Manuscript received January 11, 2008; revised manuscript received August 12, 2008, accepted August 12, 2008.

^_* Reprint requests and correspondence: Dr. Artiom Petrov, Division of Cardiology, University of California, Irvine, Medical Science Building I, Room C-116, UCI Main Campus, Irvine, California 92697 (Email: adpetrov{at}uci.edu).

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.

Key Words: matrix metalloproteinase • molecular imaging • atherosclerosis • HMG coenzyme reductase inhibitor

Abbreviations and Acronyms   %ID/g = percent total injected dose per gram of tissue   CT = computed tomography   HC = high cholesterol   MMP = matrix metalloproteinase   MPI = matrix metalloproteinase inhibitor   NZW = New Zealand White   PBS = phosphate-buffered saline   SMC = smooth muscle cell   SPECT = single-photon emission computed tomography

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J. Am. Coll. Cardiol. 2008 52: A40. [Full Text] [PDF]