Abstract 12946: Broad Spectrum Cystein Protease Inhibition Reduces Aneurysm Expansion
An abdominal aortic aneurysm (AAA) is a common dilatation disorder that may be lethal due to rupture. Current treatment relies on preventive repair of larger AAA. Yet, conventional, open repair often has a considerable morbidity and mortality, whereas endovascular AAA repair is currently not considered cost effective. Hence, pharmaceutical interventions reducing aneurysm progression, and thus reducing the need for repair could be highly beneficial. The pathology of AAA is best described as a chronic inflammatory condition that is accompanied by a protease imbalance. This excess proteolytic activity is held responsible for matrix remodelling and progressive weakening of the aortic wall. Cathepsins are associated with matrix remodelling but their engagement in aneurysm progression is discussed controversially. To test the role of cathepsins in AAA formation and the feasibility of cathepsin inhibition as a means of stabilizing AAA we evaluated the efficacy of the broad spectrum cathepsin inhibitor E64, in two established murine models of the disease. Analysis of humane AAA tissue showed a sharp increase (>1000 fold; p<0.01) in the amount of CTX fragments (representing cathepsin-mediated degradation) compared to normal aorta. Using the elastase model and the angiotesin-II model we showed that E64 treated mice profoundly reduced aneurysm formation. E64 treatment prevented loss of collagen (1.5-fold, p<0.01). In addition, comparison of the ultrasound measurements revealed that E64 significantly reduces the aortic diameter compared with NaCl-treated mice (increase of 33.3% (E64), 86.3% (NaCl); p<0.01) and with the doxycycline treated mice (diameter increase of 53.7% (doxycycline); p<0.03). Evaluation of inflammatory status showed that cathepsin inhibition results in a reduction of all inflammatory markers tested (murine interleukin 8 (KC) (4-fold, p<0.03) and interferon γ (6-fold, p<0.04). This study shows that cysteine protease inhibition prevents aneurysm formation and reduces systemic inflammation in two distinct mouse models of the disease. Cysteine protease inhibition and/or inhibition of the proton pump required for the extracellular activity of these enzymes are a potential target as pharmaceutical strategy for AAA stabilization.
- © 2011 by American Heart Association, Inc.