title: Mast cell tryptase deficiency attenuates mouse abdominal aortic aneurysm formation.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.forename: Jes S
authors.initials: JS
authors.lastname: Lindholt
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: Mark
authors.initials: M
authors.lastname: Sinnamon
authors.forename: Richard L
authors.initials: RL
authors.lastname: Stevens
authors.forename: Roberto
authors.initials: R
authors.lastname: Adachi
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Robert W
authors.initials: RW
authors.lastname: Thompson
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001012:Aorta, Abdominal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000097:blood; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006098:Granulocytes / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice; D008817:Mice, Mutant Strains; D053802:Tryptases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C509190:Tpsb2 protein, mouse; D002403:Cathepsins; D053802:Tryptases