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Critical Role Of Mast Cell Chymase In Mouse Abdominal Aortic Aneurysm Formation

J. Sun, J. Zhang, J. S. Lindholt, G. Sukhova, J. Liu, Aina He, M. Åbrink, G. Pejler, R. Stevens, R. Thompson, T. Ennis, M. Gurish, P. Libby, Guo-ping Shi
Published 2009 · Medicine

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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 KitW-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.
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