In vivo imaging of proteolytic activity in atherosclerosis

Background - 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. Methods and Results - 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. Conclusions - 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.