Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor
Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor
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DOI：
10.2967/jnumed.108.055889
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发表时间：
2009-04-01
影响因子：
9.3
通讯作者：
Narula, Jagat
中科院分区：
文献类型：
--
作者：
Ohshima, Satoru;Petrov, Artiom;Narula, Jagat
基质金属蛋白酶（MMP）在动脉粥样硬化斑块中表达，在斑块不稳定中发挥重要作用。方法：使用Tc-99m标记的广谱MMP抑制剂（MPI），我们对载脂蛋白E缺陷小鼠（ApoE（-/-），n = 14）、低密度脂蛋白受体缺陷小鼠（LDLR-/-，n = 14）和作为对照的C57/BL6小鼠（n = 7）进行MMP表达的无创成像。 7 名 ApoE(-/-) 和 7 名 LDLR-/- 接受高胆固醇饮食。体内成像后，移植主动脉，获取离体图像，并确定每克 MPI 注射剂量百分比 (%ID/g)，然后对动脉粥样硬化病变进行组织学表征。结果：通过微型 SPECT 无创地观察动脉粥样硬化病变中的 MPI 摄取，并通过微型 CT 确认解剖位置和主动脉钙化。主动脉各部分的％ID/g在高胆固醇饮食喂养的ApoE(-/-)中最高，其次是高胆固醇饮食喂养的LDLR-/-、正常饲料喂养的ApoE(-/-)和正常饲料喂养的LDLR-/-。对照小鼠的 MPI 摄取量最少。巨噬细胞 (r = 0.81，P = 0.009)、MMP-2 (r = 0.65，P = 0.013) 和 MMP-9 (r = 0.62，P = 0.008) 的 %ID/g 和 % 阳性面积之间存在显着相关性。结论：本研究证明了分子成像对于接受正常或高脂饮食的各种动脉粥样硬化转基因小鼠模型中 MMP 表达程度的无创评估的有用性。可以想象，这种策略可能会转化为鉴定不稳定的动脉粥样硬化斑块。
Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques and play an important role in plaque instability. Methods: Using Tc-99m-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.