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- Title
Deficiency of cathepsin S attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice.
- Authors
Qin, Yanwen; Cao, Xu; Guo, Jun; Zhang, Yaozhong; Pan, Lili; Zhang, Hongjia; Li, Huihua; Tang, Chaoshu; Du, Jie; Shi, Guo-Ping
- Abstract
Aims 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. Methods and 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.
- Subjects
CATHEPSINS; ANGIOTENSIN II; ABDOMINAL aortic aneurysms; APOLIPOPROTEIN E; PROTEIN deficiency; ARTERIAL surgery; EXTRACELLULAR matrix; INFLAMMATION; LABORATORY mice
- Publication
Cardiovascular Research, 2012, Vol 96, Issue 3, p401
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvs263