title: Pro-atherogenic role of smooth muscle Nox4-based NADPH oxidase.
abstract: Nox4-based NADPH oxidase is a major reactive oxygen species-generating enzyme in the vasculature, but its role in atherosclerosis remains controversial.
  
  
  OBJECTIVE
  Our goal was to investigate the role of smooth muscle Nox4 in atherosclerosis.
  
  
  RESULTS
  Atherosclerosis-prone conditions (disturbed blood flow and Western diet) increased Nox4 mRNA level in smooth muscle of arteries. To address whether upregulated smooth muscle Nox4 under atherosclerosis-prone conditions was directly involved in the development of atherosclerosis, mice carrying a human Nox4 P437H dominant negative mutation (Nox4DN), specifically in smooth muscle, were generated on a FVB/N ApoE deficient genetic background to counter the effect of increased smooth muscle Nox4. Nox4DN significantly decreased aortic stiffness and atherosclerotic lesions, with no effect on blood pressure. Gene analysis indicated that soluble epoxide hydrolase 2 (sEH) was significantly downregulated in Nox4DN smooth muscle cells (SMC), at both mRNA and protein levels. Downregulation of sEH by siRNA decreased SMC proliferation and migration, and suppressed inflammation and macrophage adhesion to SMC.
  
  
  CONCLUSIONS
  Downregulation of smooth muscle Nox4 inhibits atherosclerosis by suppressing sEH, which, at least in part, accounts for inhibition of SMC proliferation, migration and inflammation.
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China. 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: Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Zaicheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Caiyu
authors.initials: C
authors.lastname: Chen
authors.affiliation: The Nanjing Han & Zaenker Cancer Institute, OG Pharmaceuticals, Nanjing 210019, China.
authors.forename: Wanzhou
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Zhexue
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weisbrod
authors.affiliation: Vascular Biology Section, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Seta
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 812-8581, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ago
authors.affiliation: Department of Entomology & UCD Comprehensive Cancer Center, University of California-Davis, Davis, CA 95616, USA.
authors.forename: Kin Sing Stephen
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Entomology & UCD Comprehensive Cancer Center, University of California-Davis, Davis, CA 95616, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
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
authors.affiliation: Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D001794:Blood Pressure / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human
keywords: Atherosclerosis; Nox4; Smooth muscle; Soluble epoxide hydrolase 2
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