title: Cathepsin L activity is essential to elastase perfusion-induced abdominal aortic aneurysms in mice.
abstract: OBJECTIVE
  The development of abdominal aortic aneurysms (AAA) requires extensive aortic wall matrix degradation. Human AAA lesions express high levels of cathepsin L (CatL), one of the most potent mammalian elastases. Whether this protease participates directly in AAA pathogenesis, however, is unknown.
  
  
  RESULTS
  We generated experimental AAA with aortic elastase perfusion in mice and established an essential role of CatL in AAA formation. After 14 days postperfusion, most wild-type (Ctsl(+/+)) mice developed AAA, but none of the CatL-deficient (Ctsl(-/-)) mice did. AAA lesion macrophage contents, CD4(+) T cell numbers, CD31(+) and laminin-5 angiogenic fragment γ2(+) microvessel numbers, and elastin fragmentation were all significantly lower in Ctsl(-/-) mice than in Ctsl(+/+) mice. While lesions from Ctsl(-/-) mice contained fewer Ki67(+) proliferating cells than did Ctsl(+/+) mice, the absence of CatL did not affect lesion apoptotic cell contents or medial smooth-muscle cell loss significantly. Mechanistic studies indicated that the absence of CatL reduced lesion chemokine monocyte chemotactic protein-1 content, macrophage and T-cell in vitro transmigration, and angiogenesis, and altered the expression and activities of matrix metalloproteinases and other cysteinyl cathepsins in inflammatory cells, vascular cells, and AAA lesions.
  
  
  CONCLUSIONS
  CatL contributes to AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, and protease expression.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.forename: Sara
authors.initials: S
authors.lastname: Sjöberg
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Meixiang
authors.initials: M
authors.lastname: Xiang
authors.forename: Jianan
authors.initials: J
authors.lastname: Wang
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D017209:Apoptosis / Q000502:physiology; D056668:Cathepsin L / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D010196:Pancreatic Elastase / Q000009:adverse effects*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D010196:Pancreatic Elastase; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D020782:Matrix Metalloproteinases