Fujimoto Shinichiro, Hartung Dagmar, Ohshima Satoru, Edwards D Scott, Zhou Jun, Yalamanchili Padmaja, Azure Michael, Fujimoto Ai, Isobe Satoshi, Matsumoto Yuji, Boersma Hendricus, Wong Nathan, Yamazaki Junichi, Narula Navneet, Petrov Artiom, Narula Jagat
University of California, Irvine School of Medicine, Irvine, California.
Bristol-Myers Squibb, Medical Imaging, North Billerica, Massachusetts.
J Am Coll Cardiol. 2008 Dec 2;52(23):1847-1857. doi: 10.1016/j.jacc.2008.08.048.
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.
The MMP activity in atherosclerotic lesions contributes to the vulnerability of atherosclerotic plaques to rupture.
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.
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.
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.
本研究旨在评估使用锝-99m标记的广谱基质金属蛋白酶抑制剂（MPI）在实验性动脉粥样硬化中无创检测基质金属蛋白酶（MMP）活性的可行性，并确定饮食调整和他汀类药物治疗对MMP活性的影响。
动脉粥样硬化病变中的MMP活性导致动脉粥样硬化斑块易于破裂。
通过对34只新西兰白兔的腹主动脉进行球囊去内皮术并给予高胆固醇饮食来诱导动脉粥样硬化。此外，12只未进行处理的兔子用作对照，3只用于血液清除特性研究。在给予放射性标记的MPI后进行体内微型单光子发射计算机断层扫描（SPECT）成像。随后，取出主动脉以定量测量每克注射剂量百分比（%ID/g）的MPI摄取量。进行组织学和免疫组织化学表征，并通过凝胶酶谱法或酶联免疫吸附测定法确定MMP活性的程度。
通过微型SPECT成像可清晰观察到动脉粥样硬化病变（n = 18）中的MPI摄取；在注射放射性示踪剂前给予未标记的MPI后，MPI摄取明显减少（n = 4）。在停止饮食（n = 6）和氟伐他汀治疗后（n = 6），MPI摄取也显著降低；在正常对照兔中未观察到摄取（n = 12）。动脉粥样硬化病变中的%ID/g MPI摄取（0.10±0.03%）显著高于对照主动脉中的摄取（0.016±0.004%，p < 0.0001）。氟伐他汀组（0.056±0.011%，p < 0.0005）和停止饮食组（0.043±0.011%，p < 0.0001）的摄取低于未治疗组。MPI摄取与免疫组织化学证实的巨噬细胞浸润相关（r = 0.643，p < 0.0001），并且与斑块中MMP-2（r = 0.542，p < 0.0001）或MMP-9（r = 0.578，p < 0.0001）的表达相关。
目前的数据表明在动脉粥样硬化斑块中无创检测MMP活性是可行的，并证实饮食调整和他汀类药物治疗可降低MMP活性。
