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Published on: September 28, 2015
Mast cell tryptase deficiency attenuates mouse abdominal aortic aneurysm formation
Jie Zhang1, Jiusong Sun, Jes S Lindholt
1Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
Rationale:
Mast cells (MCs) contribute to the formation of abdominal aortic aneurysms (AAAs) by producing biologically active mediators. Tryptase is the most abundant MC granule protein and participates in MC activation, protease maturation, leukocyte recruitment, and angiogenesis-all processes critical to AAA pathogenesis.
Objective:
To test the hypothesis that tryptase participates directly in AAA formation.
Methods And Results:
Immunohistochemistry demonstrated enhanced tryptase staining in media and adventitia of human and mouse AAA lesions. Serum tryptase levels correlated significantly with the annual expansion rate of AAA before (r = 0.30, P = 0.003) and after (r = 0.29, P = 0.005) adjustment for common AAA risk factors in a patient follow-up study, and associated with risks for later surgical repair or overall mortality before (P = 0.009, P = 0.065) and after (P = 0.004, P = 0.001) the adjustment. Using MC protease-6-deficient mice (Mcpt6(-/-)) and aortic elastase perfusion-induced experimental AAAs, we proved a direct role of this tryptase in AAA pathogenesis. Whereas all wild-type (WT) mice developed AAA at 14 or 56 days postperfusion, Mcpt6(-/-) mice were fully protected. AAA lesions from Mcpt6(-/-) mice had fewer inflammatory and apoptotic cells, and lower chemokine levels, than did those from WT mice. MC from WT mice restored reduced AAA lesions and lesion inflammatory cell content in MC-deficient Kit(W-sh/W-sh) mice, but those prepared from Mcpt6(-/-) mice did not. Mechanistic studies demonstrated that tryptase deficiency affected endothelial cell (EC) chemokine and cytokine expression, monocyte transmigration, smooth-muscle cell apoptosis, and MC and AAA lesion cysteinyl cathepsin expression and activities.
Conclusions:
This study establishes the direct participation of MC tryptase in the pathogenesis of experimental AAAs, and suggests that levels of this protease can serve as a novel biomarker for abdominal aortic expansion.
Insights
Mast cell tryptase directly contributes to abdominal aortic aneurysm (AAA) formation. Elevated serum tryptase levels correlate with AAA expansion, suggesting its potential as a biomarker for AAA progression.
Area of Science:
- Vascular Biology
- Immunology
- Protease Function
Background:
- Mast cells (MCs) are implicated in abdominal aortic aneurysm (AAA) development through mediator production.
- Tryptase, a key MC granule protein, influences processes vital to AAA pathogenesis, including leukocyte recruitment and angiogenesis.
Purpose of the Study:
- To investigate the direct role of tryptase in the formation and progression of abdominal aortic aneurysms.
Main Methods:
- Immunohistochemistry on human and mouse AAA lesions.
- Analysis of serum tryptase levels and AAA expansion rates in patients.
- Utilizing mast cell protease-6-deficient (Mcpt6(-/-)) mice in experimental AAA models.
- Investigating the impact of tryptase deficiency on cellular and molecular pathways in AAA pathogenesis.
Main Results:
- Enhanced tryptase staining observed in human and mouse AAA lesions.
- Serum tryptase levels significantly correlated with AAA expansion rate and clinical outcomes.
- Mcpt6(-/-) mice were protected from AAA development, exhibiting reduced inflammation and apoptosis.
- Tryptase deficiency impacted endothelial cell function, monocyte transmigration, and smooth muscle cell apoptosis.
Conclusions:
- Mast cell tryptase plays a direct role in the pathogenesis of experimental AAAs.
- Serum tryptase levels may serve as a novel biomarker for monitoring abdominal aortic aneurysm expansion.
