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Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2500-8. doi: 10.1161/ATVBAHA.111.230201.

Cathepsin L activity is essential to elastase perfusion-induced abdominal aortic aneurysms in mice.

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  • 1Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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.

METHODS AND 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.

CONCLUSION:

CatL contributes to AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, and protease expression.

PMID:
21868704
[PubMed - indexed for MEDLINE]
PMCID:
PMC3312037
Free PMC Article

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