title: Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome.
abstract: Thoracic aortic aneurysm (TAA) is the life-threatening complication of Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 gene. TAA is characterized by degradation of elastic fiber, suggesting the involvement of matrix metalloproteinase (MMP)-2 and -9, the activation of which is regulated by TIMP (tissue inhibitor of MMP) types 1 and 2. We hypothesized that MMP-2 and -9 were upregulated during TAA formation in Marfan syndrome, causing loss of elastic fibers and structural integrity. We studied mice, from 3 to 12 months, heterozygous for a mutant Fbn1 allele encoding a cysteine substitution in fibrillin-1 (Fbn1(C1039G/+), designated as "Marfan" mice) (n=120), the most common class of mutation in Marfan syndrome. The littermates, Fbn1(+/+) served as controls (n=120). In Marfan aneurysmal thoracic aorta, mRNA and protein expression of MMP-2 and -9 were detected at 3 months and peaked at 6 months of age, accompanied by severe elastic fiber fragmentation and degradation. From 3 to 9 months, the MMP-2/TIMP-2 ratio increased by 43% to 63% compared with the controls. Dilated thoracic aorta demonstrated increased elasticity but distention caused a pronounced loss of contraction, suggesting weakening of the aortic wall. Breaking stress of the aneurysmal aorta was 70% of the controls. Contraction in response to depolarization and receptor stimulation decreased in the aneurysmal thoracic aorta by 50% to 80%, but the expression of alpha-smooth muscle actin between the 2 strains was not significantly different. This report demonstrates the upregulation of MMP-2 and -9 during TAA formation in Marfan syndrome. The resulting elastic fiber degeneration with deterioration of the aortic contraction and mechanical properties may explain the pathogenesis of TAA.
authors.affiliation: Child and Family Research Institute, Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada. achung@mrl.ubc.ca
authors.forename: Ada W Y
authors.initials: AW
authors.lastname: Chung
authors.forename: Karen
authors.initials: K
authors.lastname: Au Yeung
authors.forename: George G S
authors.initials: GG
authors.lastname: Sandor
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: Cornelis
authors.initials: C
authors.lastname: van Breemen
mesh_terms: D000199:Actins / Q000502:physiology; D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology; D017545:Aortic Aneurysm, Thoracic / Q000209:etiology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D008297:Male; D008382:Marfan Syndrome / Q000150:complications / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation; D015854:Up-Regulation / Q000502:physiology; D054392:Adipokines
chemical_list: D000199:Actins; D000071838:Fibrillin-1; D000071837:Fibrillins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008840:Microfilament Proteins; C000605724:Fbn1 protein, mouse; D054392:Adipokines