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(American Journal of Pathology. 2007;170:809-817.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060522

Collagen Degradation in the Abdominal Aneurysm

A Conspiracy of Matrix Metalloproteinase and Cysteine Collagenases

Hazem Abdul-Hussien^*, Ratna G.V. Soekhoe^*, Ekkehard Weber, Jan H. von der Thüsen, Robert Kleemann, Adri Mulder^*, J. Hajo van Bockel^*, Roeland Hanemaaijer and Jan H.N. Lindeman^*

From the Departments of Vascular Surgery^* and Pathology, Leiden University Medical Center, Leiden, The Netherlands; TNO-Biomedical Research, Leiden, The Netherlands; and the Institute of Physiological Chemistry, Martin-Luther-University, Halle, Germany

Growth and rupture of abdominal aortic aneurysms (AAAs) result from increased collagen turnover. Collagen turnover critically depends on specific collagenases that cleave the triple helical region of fibrillar collagen. As yet, the collagenases responsible for collagen degradation in AAAs have not been identified. Increased type I collagen degradation products confirmed collagen turnover in AAAs (median values: <1, 43, and 108 ng/mg protein in control, growing, and ruptured AAAs, respectively). mRNA and protein analysis identified neutrophil collagenase [matrix metalloproteinase (MMP)-8] and cysteine collagenases cathepsin K, L, and S as the principle collagenases in growing and ruptured AAAs. Except for modestly increased MMP-14 mRNA levels, collagenase expression was similar in growing and ruptured AAAs (anterior-lateral wall). Evaluation of posttranslational regulation of protease activity showed a threefold increase in MMP-8, a fivefold increase in cathepsins K and L, and a 30-fold increase in cathepsin S activation in growing and ruptured AAAs. The presence of the osteoclastic proton pump indicated optimal conditions for extracellular cysteine protease activity. Protease inhibitor mRNA expression was similar in AAAs and controls, but AAA protein levels of cystatin C, the principle cysteine protease inhibitor, were profoundly reduced (>80%). We found indications that this secondary deficiency relates to cystatin C degradation by (neutrophil-derived) proteases.

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