Abstract
OBJECTIVE: Cathepsin G (CatG) is a serine protease that mediates angiotensin I to angiotensin II (Ang-II) conversion and is highly expressed in human abdominal aortic aneurysms (AAAs). However, it remains untested whether this protease participates in the pathogenesis of AAA. METHODS AND RESULTS: Immunofluorescent double staining demonstrated the expression of CatG in smooth muscle cells (SMCs), macrophages, and endothelial cells in human AAA lesions (n = 12) but not in AAA-free aortas (n = 10). Whereas inflammatory cytokines induced CatG expression, high glucose concentration increased CatG activity in producing Ang-II and angiotensin-converting enzyme in SMCs, which could be fully blocked by a CatG-selective inhibitor or its small interfering RNA. To test whether CatG contributes to AAA development, we generated CatG and low-density lipoprotein receptor double deficient (Ldlr(-/-)Ctsg(-/-)) mice and their littermate controls (Ldlr(-/-)Ctsg(+/+)). Absence of CatG did not affect Ang-II infusion-induced AAAs. In contrast, in Ang-II-independent AAAs induced by periaortic CaCl2 injury (n = 12 per group), CatG deficiency significantly reduced aortic diameter increase (58.33% ± 6.83% vs 31.67% ± 5.75%; P = .007), aortic lesion area (0.35 ± 0.04 mm(2) vs 0.21 ± 0.02 mm(2); P = .005), and aortic wall elastin fragmentation grade (2.75 ± 0.18 vs 1.58 ± 0.17; P = .002) along with reduced lesion collagen content grade (2.80 ± 0.17 vs 2.12 ± 0.17; P = .009) without affecting indices of lesion inflammation, angiogenesis, cell proliferation, or apoptosis. In vitro elastin degradation assays demonstrated that CaCl2-induced AAA lesions from Ldlr(-/-)Ctsg(-/-) mice contained much lower elastinolytic activity than in those from littermate control mice. Gelatin gel zymogram assay suggested that absence of CatG in CaCl2-induced AAA lesions also reduced the activity of elastinolytic matrix metalloproteinases 2 and 9. CONCLUSIONS: CatG may contribute to CaCl2-induced experimental AAAs directly through its elastinolytic activity and indirectly by regulating lesion matrix metalloproteinases 2 and 9 activities. Increased expression of CatG in vascular and inflammatory cells of human AAAs and its increased activity in producing Ang-II and angiotensin-converting enzyme by SMCs suggest an additional mechanism by which CatG contributes to AAA lesion progression.