Abstract 2950: Imaging of Matrix Meralloproteinase Expression in Atherosclerotic Lesions in apolipoprotein E-deficient and Low-density-lipoprotein Receptor-deficient Mice
Introduction: Matrix Metalloproteinases (MMPs) contribute to fibrous cap rupture and acute coronary event. MMP production and activity constitute an important process that can be targeted by nuclear imaging for detection of vulnerable atherosclerotic lesions. Apo E-deficient (apoE-/ -) and LDL receptor-deficient (LDLR-/ -) mice exhibit hypercholesterolemia and develop complex atherosclerotic lesions similar to those seen in humans. We evaluated the feasibility of noninvasive imaging of MMP expression in experimentally induced atherosclerotic lesions of apoE-/ - and LDLR-/ - mice with or without high cholesterol diet (HC).
METHODS: Of the 35 mice used in the present study, apoE-/ - mice with HC for 6 mo (n = 7) and without (n = 7) and LDLR-/ - mice with HC for 5 mo (n = 7) and without (n = 7) were compared with 7 normal wild-type (C57BL/6) mice. 99mTc -labeled broad MMP inhibitor (MPI) was injected in all animals for noninvasive imaging using micro-SPECT/CT. After in vivo imaging, aortas were explanted to acquire ex vivo images and calculate the percentage injected dose per gram (%ID/g) MPI uptake, followed by histologic and immunohistochemical characterization.
RESULTS: The uptake of 99mTc -MPI in atherosclerotic lesions and the aortic calcification were clearly visualized noninvasively by micro-SPECT/CT. The quantitative uptake of 99mTc -labeled MPI (%ID/g) in each part of aorta was highest in the HC-fed apoE-/ - (Arch : 0.91 ± 0.28 %, thoracic aorta (Th) : 0.77 ± 0.24 %, abdominal aorta (Abd) : 0.64 ± 0.31 %) mice, followed by the HC-fed LDLR-/ - (Arch : 0.81 ± 0.40 %, Th : 0.53 ± 0.20 %, Abd : 0.49 ± 0.23 %), the normal chow-fed apoE-/ - (Arch : 0.70 ± 0.18 %, Th : 0.52 ± 0.12 %, Abd : 0.40 ± 0.14 %), the normal chow-fed LDLR-/ - (Arch : 0.48 ± 0.15 %, Th : 0.47 ± 0.15 %, Abd : 0.35 ± 0.17 %), and the control (Arch : 0.19 ± 0.05 %, Th : 0.19 ± 0.07 %, Abd : 0.15 ± 0.04 %) mice. Immunohistochemical characterization confirmed MMP-2 and 9 up-regulation and macrophage infiltration that correlated with MPI uptake.
CONCLUSION: This study demonstrates the feasibility of noninvasive imaging of atherosclerosis with radiolabeled MPI in transgenic mouse models of atherosclerosis, and suggests the possibility of development of molecular imaging for atherosclerotic plaques vulnerable to rupture.