Cysteine protease activity in the wall of abdominal aortic aneurysms

Background Cysteine proteases are potent elastolytic enzymes and together with their inhibitor, cystatin C, have been linked with the growth of abdominal aortic aneurysms (AAAs). These enzymes and their inhibitors have previously been studied in AAAs, but comparisons have always been made with wall from normal aorta. Atherosclerosis is a feature of aneurysmal disease and may therefore confound comparisons with normal wall. This study compared the expression and activity of cysteine proteases and their inhibitors in aneurysm wall with their expression in the aortic wall of patients with aortic occlusive disease (AOD). Methods: Aortic wall was obtained from 82 patients with AAA and 13 with AOD. Protein expression and activity of cathepsin B, H, K, L and S, and cystatins A, B, and C were measured by enzyme-linked immunosorbent assay and specific fluorogenic substrate assays. Matrix metalloproteinase 9 (MMP-9) activity was measured by quantitative bioimmunoassay in the same extracts. Results: AAA wall had 330% more cathepsin H protein (P = .007) and > 30% less cystatin C (P = .03) than the aortic wall from patients with AOD. The activity of cathepsins B, H, L, and S was significantly greater in AAA than AOD (376%, [P < .0001], 191%, [P = 0.019], 223%, P = 0.002, and approximately 20% [P = 0.045] respectively). MMP-9 activity was also increased in AAA compared with AOD (P < 0.0001) and levels in the wall of AAA correlated positively with cathepsin L activity (r = 0.42, P < .0001) and negatively with cystatin C (r = -0.75, P < .0001). Conclusions: The activity of four cathepsins B, H, L, and S was higher in the aneurysm wall than in aortic wall of patients with occlusive disease. This was associated with a reduced level of cystatin C in the aneurysmal wall. Cathepsin H was the only protein in which there was a correlation between protein level and activity, which suggests that post-translational modifications were responsible for activation of the other cathepsins. Increased cathepsin activity may influence the activity of MMP-9, which is thought to have an important role in aneurysm development. Clinical Relevance: The incidence of abdominal aortic aneurysms has been steadily increasing for the last 3 decades. The condition is associated with a progressive loss of structural proteins such as elastin and collagen from the wall of the aorta through increased protease activity. Metalloproteinases have been the most predominantly studied enzymes, but there is increasing evidence that other protease systems such as the cysteine proteases may also be involved. Controlling the activity of proteases may form the basis for the development of novel medical treatments that inhibit aneurysm expansion and thereby reduce the need for surgery.