Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases.
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.
Abdul-Hussien
Hazem
H
Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Soekhoe
Ratna G V
RG
Weber
Ekkehard
E
von der Thüsen
Jan H
JH
Kleemann
Robert
R
Mulder
Adri
A
van Bockel
J Hajo
JH
Hanemaaijer
Roeland
R
Lindeman
Jan H N
JH
D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology*; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D011480:Protease Inhibitors; D012333:RNA, Messenger; D003094:Collagen; D017364:Collagenases; D020782:Matrix Metalloproteinases; D003545:Cysteine