Cathepsin K deficiency reduces elastase perfusion-induced abdominal aortic aneurysms in mice

Jiusong Sun, Galina K. Sukhova, Jie Zhang, Han Chen, Sara Sjöberg, Peter Libby, Mingcan Xia, Na Xiong, Bruce D. Gelb, Guo Ping Shi

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Objective-: Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown. Methods and Results-: Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days postperfusion. CatK deficiency significantly reduced lesion CD4 + T-cell content, total lesion and medial cell proliferation and apoptosis, medial smooth muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but it did not affect AAA lesion Mac-3 + macrophage accumulation or CD31 + microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4 + T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMCs and endothelial cells but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice. Conclusion-: This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation and by affecting vascular cell protease expression and activities.

Original languageEnglish (US)
Pages (from-to)15-23
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Keywords

  • T cell
  • aneurysms
  • cathepsin K
  • elastase
  • smooth muscle cell

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Sun, J., Sukhova, G. K., Zhang, J., Chen, H., Sjöberg, S., Libby, P., Xia, M., Xiong, N., Gelb, B. D., & Shi, G. P. (2012). Cathepsin K deficiency reduces elastase perfusion-induced abdominal aortic aneurysms in mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(1), 15-23. https://doi.org/10.1161/ATVBAHA.111.235002