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(Circulation. 2009;120:973-982.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

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

Jiusong Sun, PhD^*; Jie Zhang, PhD^*; Jes S. Lindholt, MD; Galina K. Sukhova, PhD; Jian Liu, PhD; Aina He, MD; Magnus Åbrink, PhD; Gunnar Pejler, PhD; Richard L. Stevens, PhD; Robert W. Thompson, MD; Terri L. Ennis, BS; Michael F. Gurish, PhD; Peter Libby, MD; Guo-Ping Shi, DSc

From the Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (J.S., J.Z., G.K.S., J.L., A.H., R.L.S., M.F.G., P.L., G.S.); Department of Vascular Surgery, Viborg Hospital, Viborg, Denmark (J.S.L.); Department of Medical Biochemistry and Microbiology, Uppsala University (M.A.), and Department of Molecular Biosciences, Swedish University of Agricultural Sciences (G.P.), Uppsala, Sweden; and Department of Surgery, Washington University, St Louis, Mo (R.W.T., T.L.E.).

Correspondence to Guo-Ping Shi, DSc, Cardiovascular Medicine, Brigham and Women’s Hospital, NRB-7, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail gshi{at}rics.bwh.harvard.edu

Received January 8, 2009; accepted June 29, 2009.

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 120: 919-920. [Extract] [Full Text]