Skip to main content
SLU publication database (SLUpub)

Research article2009Peer reviewedOpen access

Critical Role of Mast Cell Chymase in Mouse Abdominal Aortic Aneurysm Formation

Sun, Jiusong; Zhang, Jie; Lindholt, Jes S.; Sukhova, Galina K.; Liu, Jian; He, Aina; Abrink, Magnus; Pejler, Gunnar; Stevens, Richard L.; Thompson, Robert W.; Ennis, Terri L.; Gurish, Michael F.; Libby, Peter; Shi, Guo-Ping

Abstract

Background-Mast cell chymase may participate in the pathogenesis of human abdominal aortic aneurysm (AAA), yet a direct contribution of this serine protease to AAA formation remains unknown.Methods and Results-Human AAA lesions had high numbers of chymase-immunoreactive mast cells. Serum chymase level correlated with AAA growth rate (P=0.009) in a prospective clinical study. In experimental AAA produced by aortic elastase perfusion in wild-type (WT) mice or those deficient in the chymase ortholog mouse mast cell protease-4 (mMCP-4) or deficient in mMCP-5 (Mcpt4(-/-), Mcpt5(-/-)), Mcpt4(-/-) but not Mcpt5(-/-) had reduced AAA formation 14 days after elastase perfusion. Even 8 weeks after perfusion, aortic expansion in Mcpt4(-/-) mice fell by 50% compared with that of the WT mice (P=0.0003). AAA lesions in Mcpt4(-/-) mice had fewer inflammatory cells and less apoptosis, angiogenesis, and elastin fragmentation than those of WT mice. Although Kit(W-sh/W-sh) mice had protection from AAA formation, reconstitution with mast cells from WT mice, but not those from Mcpt4(-/-) mice, partially restored the AAA phenotype. Mechanistic studies suggested that mMCP-4 regulates expression and activation of cysteine protease cathepsins, elastin degradation, angiogenesis, and vascular cell apoptosis.Conclusions-High chymase-positive mast cell content in human AAA lesions, greatly reduced AAA formation in Mcpt4(-/-) mice, and significant correlation of serum chymase levels with human AAA expansion rate suggests participation of mast cell chymase in the progression of human and mouse AAA. (Circulation. 2009; 120: 973-982.)

Keywords

aneurysm; animal model; chymase; mast cells

Published in

Circulation
2009, Volume: 120, number: 11, pages: 973-982

      UKÄ Subject classification

      Cardiac and Cardiovascular Systems
      Cell and Molecular Biology

      Publication identifier

      DOI: https://doi.org/10.1161/CIRCULATIONAHA.109.849679

      Permanent link to this page (URI)

      https://res.slu.se/id/publ/28024