title: Increased expression of Nox1 in neointimal smooth muscle cells promotes activation of matrix metalloproteinase-9.
abstract: OBJECTIVE
  Vascular injury causes neointimal hypertrophy, which is characterized by redox-mediated matrix degradation and smooth muscle cell (SMC) migration and proliferation. We hypothesized that, as compared to the adjacent medial SMCs, neointimal SMCs produce increased superoxide via NADPH oxidase, which induces redox-sensitive intracellular signaling to activate matrix metalloproteinase-9 (MMP-9).
  
  
  RESULTS
  Two weeks after balloon injury, rat aorta developed a prominent neointima, containing increased expression of NADPH oxidase and reactive oxygen species (ROS) as compared to the medial layer. Next, SMCs were isolated from either the neointima or the media and studied in culture. Neointimal-derived SMCs exhibited increased Nox1 expression and ROS levels as compared to medial SMCs. Neointimal SMCs had higher cell growth rates than medial SMCs. ROS-dependent ERK1/2 phosphorylation was greater in neointimal SMCs. MMP-9 activity, as detected by gel zymography, was greater in neointimal SMCs under resting and stimulated conditions and was prevented by expression of an antisense to Nox1 or treatment with an ERK1/2 inhibitor.
  
  
  CONCLUSIONS
  Following vascular injury, the increased expression of Nox1 in SMCs within the neointima initiates redox-dependent phosphorylation of ERK1/2 and subsequent MMP-9 activation.
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Xu
authors.forename: Amy S
authors.initials: AS
authors.lastname: Shriver
authors.forename: Dammanahalli K
authors.initials: DK
authors.lastname: Jagadeesha
authors.forename: Ali H
authors.initials: AH
authors.lastname: Chamseddine
authors.forename: Katalin
authors.initials: K
authors.lastname: Szőcs
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Bhalla
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Miller
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000502:physiology*; D000074624:NADPH Oxidase 1; D058426:Neointima / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614712:NOX1 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat