P324	A destabilising role for cathepsin S in murine and human atherosclerotic plaques.
1K.Rodgers, 1D.Watkins, 1A.Miller, 2P.Chan, 3W.Brissette, 4C.Long, 1Chr.Jackson
1Bristol Heart Institute, Bristol, GB; 2Heart Research Institute, Sydney, AU; 3Pfizer, Groton, US; 4Pfizer, Sandwich, GB.

Lysosomal proteinases have been implicated in a number of pathologies associated with extracellular matrix breakdown. We have therefore investigated the possibility that the lysosomal proteinase cathepsin S may destabilise atherosclerotic plaques. The cysteine proteinase inhibitor, egg white cystatin, was biotinylated and used as an active-site-directed probe for cathepsins. Biotinylated cystatin selectively detected cathepsin S on Western (affinity) blots of extracts of human carotid atherosclerotic plaque. Active cathepsin S was detectable in extracts of human atherosclerotic plaque but not in non-diseased carotid arteries. Active cathepsins were especially prominent in macrophages in the shoulder regions of plaques, areas considered to be vulnerable to rupture. Cathepsin S protein co-localised with regions of elastin degradation in human coronary plaques. Apolipoprotein E/cathepsin S double knockout mice had 69% fewer ruptures in the brachiocephalic artery than their age-, strain- and sex-matched apolipoprotein E single knockout littermate controls (p<0.001). These data suggest that cathepsin S plays an important role in atherosclerotic plaque destabilisation in both mice and humans.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.