title: Important role of the angiotensin II pathway in producing matrix metalloproteinase-9 in human thoracic aortic aneurysms.
abstract: BACKGROUND
  The precise pathologic mechanisms underlying human thoracic aortic aneurysms (TAAs) remain uncertain, except that matrix metalloproteinase-9 (MMP-9) is considered a key enzyme for the degradation of extracellular matrix in aneurysm walls. The aim of this study was to elucidate the significance of the angiotensin II (AngII) pathway to MMP-9 production in human TAA walls.
  
  
  RESULTS
  We examined the activation of Smad2, a common downstream molecule of AngII and transforming growth factor β (TGF-β) pathways, and the expression of MMP-9 in human nonsyndromic TAA walls. We observed significant increases in Smad2 activation and MMP-9 expression, associated with disruption of elastic lamellae. Using human TAA walls in ex vivo culture, we investigated whether AngII and/or TGF-β pathways are essential for MMP-9 production. Unexpectedly, TGF-β receptor inhibitor had no effect on MMP-9 production. We used PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) activation, and demonstrated that PD98059 dramatically reduced MMP-9 production with attenuation of Smad2 activation. Moreover, exogenous AngII resulted in increases in Smad2 activation and MMP-9 production, in an ERK-dependent manner.
  
  
  CONCLUSIONS
  Our findings indicate that the AngII/ERK pathway has an important role in the production of MMP-9 in human nonsyndromic TAA walls.
authors.affiliation: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nagasawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Akihito
authors.initials: A
authors.lastname: Mikamo
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamashita
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Masanori
authors.initials: M
authors.lastname: Tsuchida
authors.forename: Kimikazu
authors.initials: K
authors.lastname: Hamano
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D017545:Aortic Aneurysm, Thoracic / Q000201:enzymology*; D006801:Humans; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9