Critical role of mast cell chymase in mouse abdominal aortic aneurysm formation

Background - Mast cell chymase may participate in the pathogenesis of human abadminal 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.