Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor
Satoru Ohshima 1,
Artiom Petrov 1*,
Shinichiro Fujimoto 1,
Jun Zhou 1,
Michael Azure 2,
D. Scott Edwards 2,
Toyoaki Murohara 3,
Navneet Narula 1,
Sotirios Tsimikas 4,
and
Jagat Narula 1
1 Division of Cardiology, University of California, Irvine School of Medicine, Irvine, California
2 Lantheus Medical Imaging, North Billerica, Massachusetts
3 Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
4 Division of Cardiovascular Diseases, Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California
* To whom correspondence should be addressed. E-mail: adpetrov{at}uci.edu.
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Abstract |
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Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques and play an important role in plaque instability. Methods: Using 99mTc-labeled broad-spectrum MMP inhibitor (MPI), we performed noninvasive imaging of MMP expression with micro-SPECT/micro-CT in mice deficient in apolipoprotein E (ApoE-/-, n = 14), mice deficient in low-density-lipoprotein receptor (LDLR-/-, n = 14), and C57/BL6 mice as controls (n = 7). Seven ApoE-/- and 7 LDLR-/- received a high-cholesterol diet. After in vivo imaging, aortas were explanted, ex vivo images acquired, and the percent injected dose of MPI per gram (%ID/g) determined, followed by histologic characterization of atherosclerotic lesions. Results: MPI uptake was noninvasively visualized in atherosclerotic lesions by micro-SPECT, with confirmation by micro-CT of anatomic location and aortic calcification. %ID/g in each part of the aorta was highest in ApoE-/- that were fed a high-cholesterol diet, followed by LDLR-/- that were fed a high-cholesterol diet, ApoE-/- that were fed normal chow, and LDLR-/- that were fed normal chow. The control mice had minimal MPI uptake. A significant correlation was noted between %ID/g and % area positive for macrophages (r = 0.81, P = 0.009), MMP-2 (r = 0.65, P = 0.013), and MMP-9 (r = 0.62, P = 0.008). Conclusion: This study demonstrates the usefulness of molecular imaging for noninvasive assessment of the extent of MMP expression in various transgenic mouse models of atherosclerosis receiving a normal or hyperlipidemic diet. It is conceivable that such a strategy may be translationally developed for identification of unstable atherosclerotic plaques.
Key Words:
radionuclide imaging, atherosclerosis, plaque rupture, apolipoprotein E–deficient mice, low-density-lipoprotein receptor–deficient mice
