Molecular imaging of matrix metalloproteinase expression in atherosclerotic plaques of mice deficient in apolipoprotein e or low-density-lipoprotein receptor.
Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques and play an important role in plaque instability.


METHODS
Using (99m)Tc-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).


CONCLUSIONS
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.
Ohshima
Satoru
S
Division of Cardiology, University of California, Irvine School of Medicine, Irvine, California, USA.
Petrov
Artiom
A
Fujimoto
Shinichiro
S
Zhou
Jun
J
Azure
Michael
M
Edwards
D Scott
DS
Murohara
Toyoaki
T
Narula
Navneet
N
Tsimikas
Sotirios
S
Narula
Jagat
J
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D013667:Technetium / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D001057:Apolipoproteins E; D015415:Biomarkers; D061965:Matrix Metalloproteinase Inhibitors; D019275:Radiopharmaceuticals; D011973:Receptors, LDL; D013667:Technetium; D020782:Matrix Metalloproteinases