Chen Jiqiu, Tung Ching-Hsuan, Mahmood Umar, Ntziachristos Vasilis, Gyurko Robert, Fishman Mark C, Huang Paul L, Weissleder Ralph
Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Circulation. 2002 Jun 11;105(23):2766-71. doi: 10.1161/01.cir.0000017860.20619.23.
Atherosclerotic plaque rupture, the most important cause of acute cardiovascular incidents, has been strongly associated with vascular inflammation. On the basis of the hypothesis that the inflammatory response and proteolysis lead to plaque rupture, we have examined the role of cathepsin B as a model proteolytic enzyme.
Using western-type diet-fed apoE and apoE/endothelial NO synthase double knockout mice as models of atherosclerosis, we show (1) that cathepsin B is upregulated in atherosclerotic lesions characterized by high degrees of inflammation compared with normal aorta or silent lesions, (2) that intravenously injectable novel cathepsin B imaging beacons are highly activated within active atherosclerotic lesions and colocalize with cathepsin B immunoreactivity, and (3) that cathepsin B activity in atherosclerotic lesions can be imaged in whole animals by using a novel near-infrared tomographic imaging system.
These studies indicate that cathepsin B, and potentially other proteases, may serve as a biomarker for vulnerable plaques when probed with beacons. The tomographic in vivo imaging method as well as catheter-based optical sensing methods could be readily adapted to screening and potentially to the molecular profiling of a number of proteases in vulnerable plaque in vivo.
动脉粥样硬化斑块破裂是急性心血管事件的最重要原因，与血管炎症密切相关。基于炎症反应和蛋白水解导致斑块破裂的假说，我们研究了组织蛋白酶B作为一种典型蛋白水解酶的作用。
以喂食西式饮食的载脂蛋白E和载脂蛋白E/内皮型一氧化氮合酶双敲除小鼠作为动脉粥样硬化模型，我们发现：（1）与正常主动脉或无症状斑块相比，在以高度炎症为特征的动脉粥样硬化病变中，组织蛋白酶B表达上调；（2）静脉注射的新型组织蛋白酶B成像示踪剂在活跃的动脉粥样硬化病变内高度活化，并与组织蛋白酶B免疫反应性共定位；（3）使用新型近红外断层成像系统可在整体动物中对动脉粥样硬化病变中的组织蛋白酶B活性进行成像。
这些研究表明，当用示踪剂检测时，组织蛋白酶B以及其他潜在的蛋白酶可能作为易损斑块的生物标志物。断层成像体内成像方法以及基于导管的光学传感方法可很容易地应用于体内易损斑块中多种蛋白酶的筛选及潜在的分子分析。
