title: Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm.
abstract: BACKGROUND
  Marfan syndrome (MS) is a genetic disorder caused by a mutation in the fibrillin gene FBN1. Bicuspid aortic valve (BAV) is a congenital heart malformation of unknown cause. Both conditions are associated with ascending aortic aneurysm and premature death. This study examined the relationship among the secretion of extracellular matrix proteins fibrillin, fibronectin, tenascin, and vascular smooth muscle cell (VSMC) apoptosis. The role of matrix metalloproteinase (MMP)-2 in VSMC apoptosis was studied in MS aneurysm.
  
  
  RESULTS
  Aneurysm tissue was obtained from patients undergoing surgery (MS: 4 M, 1 F, age 27-45 years; BAV: 3 M, 2 F, age 28-65 years). Normal aorta from subjects with nonaneurysm disease was also collected (4 M, 1 F, age 23-93 years). MS and BAV aneurysm histology showed areas of cystic medial necrosis (CMN) without inflammatory infiltrate. Immunohistochemical study of cultured MS and BAV VSMC showed intracellular accumulation and reduction of extracellular distribution of fibrillin, fibronectin, and tenascin. Western blot showed no increase in expression of fibrillin, fibronectin, or tenascin in MS or BAV VSMC and increased expression of MMP-2 in MS VSMCs. There was 4-fold increase in loss of cultured VSMC incubated in serum-free medium for 24 hours in both MS (27+/-8%) and BAV (32+/-14%) compared with control (7+/-5%).
  
  
  CONCLUSIONS
  In MS and BAV there is alteration in both the amount and quality of secreted proteins and an increased degree of VSMC apoptosis. Up-regulation of MMP-2 might play a role in VSMC apoptosis in MS VSMC. The findings suggest the presence of a fundamental cellular abnormality in BAV thoracic aorta, possibly of genetic origin.
authors.affiliation: Department of Medicine, University of Queensland, Prince Charles Hospital, Brisbane, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Nataatmadja
authors.forename: Malcolm
authors.initials: M
authors.lastname: West
authors.forename: Jenny
authors.initials: J
authors.lastname: West
authors.forename: Kim
authors.initials: K
authors.lastname: Summers
authors.forename: Philip
authors.initials: P
authors.lastname: Walker
authors.forename: Michio
authors.initials: M
authors.lastname: Nagata
authors.forename: Teruo
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D000368:Aged; D017545:Aortic Aneurysm, Thoracic / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D001021:Aortic Valve / Q000002:abnormalities*; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D005353:Fibronectins / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008382:Marfan Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D008840:Microfilament Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D019063:Tenascin / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D054392:Adipokines
chemical_list: D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D005353:Fibronectins; D020778:Matrix Metalloproteinase 2; D008840:Microfilament Proteins; D019063:Tenascin; C000605722:FBN1 protein, human; D054392:Adipokines