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

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. Human AAA lesions had high numbers of chymase-immunoreactive mast cells. Serum chymase level correlated with AAA growth...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2009-09, Vol.120 (11), p.973-982
Main Authors: JIUSONG SUN, JIE ZHANG, ENNIS, Terri L, GURISH, Michael F, LIBBY, Peter, SHI, Guo-Ping, LINDHOLT, Jes S, SUKHOVA, Galina K, JIAN LIU, AINA HE, ABRINK, Magnus, PEJLER, Gunnar, STEVENS, Richard L, THOMPSON, Robert W
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
aneurysm
animal model
Animals
Aortic Aneurysm, Abdominal - immunology
Aortic Aneurysm, Abdominal - metabolism
Aortic Aneurysm, Abdominal - pathology
Apoptosis - immunology
Biological and medical sciences
Blood and lymphatic vessels
Cardiac and Cardiovascular Systems
Cardiology. Vascular system
Cathepsins - metabolism
Cell and Molecular Biology
Cell- och molekylärbiologi
chymase
Chymases - genetics
Chymases - immunology
Chymases - metabolism
Disease Models, Animal
Diseases of the aorta
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
Female
Gene Expression Regulation, Enzymologic - immunology
Humans
Kardiologi
Macrophages - pathology
Male
mast cells
Mast Cells - enzymology
Mast Cells - immunology
Medical sciences
MEDICIN
MEDICINE
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Microcirculation
Middle Aged
Muscle, Smooth, Vascular - enzymology
Muscle, Smooth, Vascular - immunology
Serine Endopeptidases - genetics
Serine Endopeptidases - immunology
Serine Endopeptidases - metabolism
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Summary: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. 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. 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.
ISSN:0009-7322
1524-4539
1524-4539
DOI:10.1161/circulationaha.109.849679