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Critical role of mast cell chymase in mouse abdominal aortic aneurysm formation
Jiusong Sun1, Jie Zhang, Jes S Lindholt
1Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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.
Insights
Mast cell chymase contributes to abdominal aortic aneurysm (AAA) progression. Studies show reduced AAA formation in mice lacking mouse mast cell protease-4 (mMCP-4), suggesting mMCP-4 as a therapeutic target.
Area of Science:
- Vascular Biology
- Protease Function in Disease
Background:
- Mast cell chymase's role in abdominal aortic aneurysm (AAA) pathogenesis is suspected but not directly established.
- The specific contribution of this serine protease to AAA formation requires elucidation.
Purpose of the Study:
- To investigate the direct role of mast cell chymase, specifically mouse mast cell protease-4 (mMCP-4), in the development and progression of abdominal aortic aneurysms (AAA).
Main Methods:
- Human AAA lesions were analyzed for mast cell chymase.
- Serum chymase levels were correlated with AAA growth in a clinical study.
- Experimental AAA was induced in wild-type (WT) mice and mice deficient in mMCP-4 (Mcpt4(-/-)) or mMCP-5 (Mcpt5(-/-)) using elastase perfusion.
- AAA formation, aortic expansion, inflammatory cell infiltration, apoptosis, angiogenesis, and elastin fragmentation were assessed.
- Mast cell reconstitution experiments were performed in Kit(W-sh/W-sh) mice.
Main Results:
- Human AAA lesions exhibited high numbers of chymase-immunoreactive mast cells.
- Serum chymase levels positively correlated with AAA growth rate (P=0.009).
- Mcpt4(-/-) mice showed significantly reduced AAA formation (50% less aortic expansion at 8 weeks) and decreased lesion inflammation, apoptosis, angiogenesis, and elastin fragmentation compared to WT mice.
- Mcpt5(-/-) mice did not show reduced AAA formation.
- Mast cell reconstitution with WT mast cells, but not Mcpt4(-/-) mast cells, partially restored the AAA phenotype in Kit(W-sh/W-sh) mice.
- Mechanistic studies indicated mMCP-4 regulates cysteine proteases, elastin degradation, angiogenesis, and vascular cell apoptosis.
Conclusions:
- High mast cell chymase content in human AAA lesions, reduced AAA formation in Mcpt4(-/-) mice, and the correlation between serum chymase and AAA expansion rate strongly suggest mast cell chymase's involvement in AAA progression.
- Mouse mast cell protease-4 (mMCP-4) plays a critical role in AAA development and progression by influencing key pathological processes.
