title: Endothelial NADPH oxidase 4 protects ApoE-/- mice from atherosclerotic lesions.
abstract: Vascular reactive oxygen species (ROS) are known to be involved in atherosclerosis development and progression. NADPH oxidase 4 (Nox4) is a constitutively active ROS-producing enzyme that is highly expressed in the vascular endothelium. Nox4 is unique in its biology and has been implicated in vascular repair, however, the role of Nox4 in atherosclerosis is unknown. Therefore, to determine the effect of endothelial Nox4 on development of atherosclerosis, Apoe E-/- mice +/- endothelial Nox4 (ApoE-/- + EC Nox4) were fed a high cholesterol/high fat (Western) diet for 24 weeks. Significantly fewer atherosclerotic lesions were observed in the ApoE-/- + EC Nox4 mice as compared to the ApoE-/- littermates, which was most striking in the abdominal region of the aorta. In addition, markers of T cell populations were markedly different between the groups; T regulatory cell marker (FoxP3) was increased whereas T effector cell marker (T-bet) was decreased in aorta from ApoE-/- + EC Nox4 mice compared to ApoE-/- alone. We also observed decreased monokine induced by gamma interferon (MIG; CXCL9), a cytokine known to recruit and activate T cells, in plasma and tissue from ApoE-/- + EC Nox4 mice. To further investigate the link between endothelial Nox4 and MIG expression, we utilized cultured endothelial cells from our EC Nox4 transgenic mice and human cells with adenoviral overexpression of Nox4. In these cultured cells, upregulation of Nox4 attenuated endothelial cell MIG expression in response to interferon-gamma. Together these data suggest that endothelial Nox4 expression reduces MIG production and promotes a T cell distribution that favors repair over inflammation, leading to protection from atherosclerosis.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: siobhan.craige@umassmed.edu.
authors.forename: Siobhan M
authors.initials: SM
authors.lastname: Craige
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Shashi
authors.initials: S
authors.lastname: Kant
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Michaella
authors.initials: M
authors.lastname: Reif
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Angoff
authors.affiliation: Department of Cardiovascular Medicine, Kumamoto University Hospital, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugamura
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Fitzgibbons
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001057:Apolipoproteins E / Q000502:physiology*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D007371:Interferon-gamma; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: Atherosclerosis; CXCL9; NADPH Oxidase 4; Reactive oxygen species; T regulatory cells