title: Role of smooth muscle Nox4-based NADPH oxidase in neointimal hyperplasia.
abstract: Elevated levels of reactive oxygen species (ROS) in the vascular wall play a key role in the development of neointimal hyperplasia. Nox4-based NADPH oxidase is a major ROS generating enzyme in the vasculature, but its roles in neointimal hyperplasia remain unclear.
  
  
  OBJECTIVE
  Our purpose was to investigate the role of smooth muscle cell (SMC) Nox4 in neointimal hyperplasia.
  
  
  RESULTS
  Mice overexpressing a human Nox4 mutant form, carrying a P437H dominant negative mutation (Nox4DN) and driven by SM22α promoter, to achieve specific expression in SMC, were generated in a FVB/N genetic background. After wire injury-induced endothelial denudation, Nox4DN had significantly decreased neointima formation compared with non-transgenic littermate controls (NTg). ROS production, serum-induced proliferation and migration, were significantly decreased in aortic SMCs isolated from Nox4DN compared with NTg. Both mRNA and protein levels of thrombospondin 1 (TSP1) were significantly downregulated in Nox4DN SMCs. Downregulation of TSP1 by siRNA decreased cell proliferation and migration in SMCs. Similar to Nox4DN, downregulation of Nox4 by siRNA significantly decreased TSP1 expression level, cell proliferation and migration in SMCs.
  
  
  CONCLUSIONS
  Downregulation of smooth muscle Nox4 inhibits neointimal hyperplasia by suppressing TSP1, which in part can account for inhibition of SMC proliferation and migration.
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China; Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: xiaoyongtong@cqu.edu.cn.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Tong
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Alok R
authors.initials: AR
authors.lastname: Khandelwal
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; Department of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Zhexue
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA; Department of Cardiology, TongJi Hospital, Wuhan 430030, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan; Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ago
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cohen
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006965:Hyperplasia; D008297:Male; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D058426:Neointima / Q000201:enzymology* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse
keywords: Neointimal hyperplasia; Nox4; Smooth muscle cell; Thrombospondin 1