Research article summary (published 29 Aug 2009):

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

Full 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.

Author information

Author/s: Sun, Jiusong (J); 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);

Affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Grants: HL083762 (Agency:NHLBI NIH HHS) ; HL36110 (Agency:NHLBI NIH HHS) ; HL56701 (Agency:NHLBI NIH HHS) ; HL56985 (Agency:NHLBI NIH HHS) ; HL60942 (Agency:NHLBI NIH HHS) ; HL81090 (Agency:NHLBI NIH HHS) ; HL88547 (Agency:NHLBI NIH HHS) ; R01 HL060942-10A1 (Agency:NHLBI NIH HHS) ; R01 HL081090-02 (Agency:NHLBI NIH HHS) ; R01 HL088547-02 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Circulation (Circulation), published in United States. (Language: eng)

Reference: 2009-Sep; vol 120 (issue 11) : pp 973-82

Dates: Created 2009/09/15; Completed 2009/10/08;

PMID: 19720934, status: MEDLINE (last retrieval date: 10/8/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adult Aged Aged, 80 and over Animals Aortic Aneurysm, Abdominal - immunology; metabolism; pathology Apoptosis - immunology Cathepsins - metabolism Chymases - genetics; immunology; metabolism Disease Models, Animal Female Gene Expression Regulation, Enzymologic - immunology

Humans Macrophages - pathology Male Mast Cells - enzymology; immunology Mice Mice, Inbred C57BL Mice, Mutant Strains Microcirculation Middle Aged Muscle, Smooth, Vascular - enzymology; immunology Serine Endopeptidases - genetics; immunology; metabolism

Associated Chemicals: Cathepsins (EC 3.4.-) ; Cma1 protein, mouse (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-) ; mast cell protease 4 (EC 3.4.21.-) ; Chymases (EC 3.4.21.39) ; cathepsin S (EC 3.4.22.27)

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