title: Endothelial Nox4-based NADPH oxidase regulates atherosclerosis via soluble epoxide hydrolase.
abstract: Nox4-based NADPH oxidase is a major reactive oxygen species-generating enzyme in the vasculature, but its role in atherosclerosis remains controversial.
  
  
  
  Our goal was to investigate the mechanisms of endothelial Nox4 in regulating atherosclerosis.
  
  
  
  Atherosclerosis-prone conditions (disturbed blood flow, type I diabetes, and Western diet) downregulated endothelial Nox4 mRNA in arteries. To address whether the downregulated endothelial Nox4 was directly involved in the development of atherosclerosis, we generated mice carrying a human Nox4 P437H dominant negative mutation (Nox4DN), driven by the endothelial specific promoter Tie-2, on atherosclerosis-prone genetic background (ApoE deficient mice) to mimic the effect of decreased endothelial Nox4. Nox4DN significantly increased type I diabetes-induced aortic stiffness and atherosclerotic lesions. Gene analysis indicated that soluble epoxide hydrolase 2 (sEH) was significantly upregulated in Nox4DN endothelial cells (EC). Inhibition of sEH activity in Nox4DN EC suppressed inflammation and macrophage adhesion to EC. On the contrary, overexpression of endothelial wild type Nox4 suppressed sEH, ameliorated Western diet-induced atherosclerosis and decreased aortic stiffness.
  
  
  
  Atherosclerosis-prone conditions downregulated endothelial Nox4 to accelerate the progress of atherosclerosis, at least in part, by upregulating sEH to enhance inflammation.
authors.affiliation: Innovative Drug Research Centre, Chongqing University, Chongqing 401331, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Hu
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.
authors.forename: Alok R
authors.initials: AR
authors.lastname: Khandelwal
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: Zaicheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Wuhan EasyDiagnosis Biomedicine Co., Ltd., Wuhan 430075, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
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: 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: Department of Entomology & UCD Comprehensive Cancer Center, University of California-Davis, Davis, CA 95616, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Kin Sing Stephen
authors.initials: KSS
authors.lastname: Lee
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 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: 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
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
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D000074663:NADPH Oxidase 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000074663:NADPH Oxidase 4; C422943:Nox4 protein, mouse; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse
keywords: Atherosclerosis; Endothelium; Nox4; Soluble epoxide hydrolase 2; Type I diabetes