title: Deficiency of cathepsin S attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  Abdominal aortic aneurysm (AAA) is characterized by extensive aortic wall matrix degradation that contributes to the remodelling and eventual rupture of the arterial wall. Elastinolytic cathepsin S (Cat S) is highly expressed in human aneurysmal lesions, but whether it contributes to the pathogenesis of AAA remains unknown.
  
  
  RESULTS
  AAAs were induced in apolipoprotein E (ApoE) and Cat S compound mutant (Apoe(-/-)Ctss(-/-)) mice and in ApoE-deficient Cat S wild-type littermates (Apoe(-/-)Ctss(+/+)) by chronic angiotensin II infusion, and AAA lesions were analysed after 28 days. We found that Cat S expression increased significantly in mouse AAA lesions. The AAA incidence in Apoe(-/-)Ctss(-/-) mice was much lower than that in Apoe(-/-)Ctss(+/+) mice (10 vs. 80%). Cat S deficiency significantly reduced external and luminal abdominal aortic diameters, medial elastin fragmentation, and adventitia collagen content. Cat S deficiency reduced aortic lesion expression and the activity of matrix metalloproteinase (MMP)-2, MMP-9, and Cat K, but not the activity of other major cathepsins, such as Cat B and Cat L. Absence of Cat S significantly reduced AAA lesion media smooth muscle cell (SMC) apoptosis, lesion adventitia microvessel content, and inflammatory cell accumulation and proliferation. In vitro studies proved that Cat S helps promote SMC apoptosis, angiogenesis, monocyte and T-cell transmigration, and T-cell proliferation--all of which are essential to AAA pathogenesis.
  
  
  CONCLUSIONS
  These data provide direct evidence that Cat S plays an important role in AAA formation and suggest that Cat S is a new therapeutic target for human AAA.
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases,  Beijing An Zhen Hospital, Capital Medical University, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing 100029,  China.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Qin
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Yaozhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lili
authors.initials: L
authors.lastname: Pan
authors.forename: Hongjia
authors.initials: H
authors.lastname: Zhang
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.forename: Chaoshu
authors.initials: C
authors.lastname: Tang
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism; D056657:Cathepsin K / Q000378:metabolism; D002403:Cathepsins / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D017252:CD3 Complex; D000804:Angiotensin II; D003094:Collagen; D004549:Elastin; D002403:Cathepsins; C028217:cathepsin S; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse