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


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.
Sun
Jiusong
J
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Zhang
Jie
J
Lindholt
Jes S
JS
Sukhova
Galina K
GK
Liu
Jian
J
He
Aina
A
Abrink
Magnus
M
Pejler
Gunnar
G
Stevens
Richard L
RL
Thompson
Robert W
RW
Ennis
Terri L
TL
Gurish
Michael F
MF
Libby
Peter
P
Shi
Guo-Ping
GP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000276:immunology; D002403:Cathepsins / Q000378:metabolism; D053818:Chymases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008833:Microcirculation; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000276:immunology; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D002403:Cathepsins; C509227:Cma1 protein, mouse; D012697:Serine Endopeptidases; C066932:mast cell protease 4; D053818:Chymases; C028217:cathepsin S