Mast cell tryptase deficiency attenuates mouse abdominal aortic aneurysm formation

Jie Zhang, Jiusong Sun, Jes S. Lindholt, Galina K. Sukhova, Mark Sinnamon, Richard L. Stevens, Roberto Adachi, Peter Libby, Robert W. Thompson, Guo Ping Shi

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Rationale: Mast cells (MCs) contribute to the formation of abdominal aortic aneurysms (AAAs) by producing biologically active mediators. Tryptase is the most abundant MC granule protein and participates in MC activation, protease maturation, leukocyte recruitment, and angiogenesis-all processes critical to AAA pathogenesis. Objective: To test the hypothesis that tryptase participates directly in AAA formation. Methods and results: Immunohistochemistry demonstrated enhanced tryptase staining in media and adventitia of human and mouse AAA lesions. Serum tryptase levels correlated significantly with the annual expansion rate of AAA before (r=0.30, P=0.003) and after (r=0.29, P=0.005) adjustment for common AAA risk factors in a patient follow-up study, and associated with risks for later surgical repair or overall mortality before (P=0.009, P=0.065) and after (P=0.004, P=0.001) the adjustment. Using MC protease-6-deficient mice (Mcpt6) and aortic elastase perfusion-induced experimental AAAs, we proved a direct role of this tryptase in AAA pathogenesis. Whereas all wild-type (WT) mice developed AAA at 14 or 56 days postperfusion, Mcpt6 mice were fully protected. AAA lesions from Mcpt6 mice had fewer inflammatory and apoptotic cells, and lower chemokine levels, than did those from WT mice. MC from WT mice restored reduced AAA lesions and lesion inflammatory cell content in MC-deficient Kit mice, but those prepared from Mcpt6 mice did not. Mechanistic studies demonstrated that tryptase deficiency affected endothelial cell (EC) chemokine and cytokine expression, monocyte transmigration, smooth-muscle cell apoptosis, and MC and AAA lesion cysteinyl cathepsin expression and activities. Conclusions: This study establishes the direct participation of MC tryptase in the pathogenesis of experimental AAAs, and suggests that levels of this protease can serve as a novel biomarker for abdominal aortic expansion.

Original languageEnglish
Pages (from-to)1316-1327
Number of pages12
JournalCirculation research
Volume108
Issue number11
DOIs
StatePublished - May 27 2011

Keywords

  • T cell
  • abdominal aortic aneurysm
  • apoptosis
  • mMCP-6
  • macrophage
  • tryptase

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    Zhang, J., Sun, J., Lindholt, J. S., Sukhova, G. K., Sinnamon, M., Stevens, R. L., Adachi, R., Libby, P., Thompson, R. W., & Shi, G. P. (2011). Mast cell tryptase deficiency attenuates mouse abdominal aortic aneurysm formation. Circulation research, 108(11), 1316-1327. https://doi.org/10.1161/CIRCRESAHA.111.243758