title: Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo.
abstract: OBJECTIVE
  Lectin-like oxLDL receptor-1 (LOX-1) mediates the uptake of oxidized low-density lipoprotein (oxLDL) in endothelial cells and macrophages. However, the different atherogenic potential of LOX-1-mediated endothelial and macrophage oxLDL uptake remains unclear. The present study was designed to investigate the in vivo role of endothelial LOX-1 in atherogenesis.
  
  
  RESULTS
  Endothelial-specific LOX-1 transgenic mice were generated using the Tie2 promoter (LOX-1TG). Oxidized low-density lipoprotein uptake was enhanced in cultured endothelial cells, but not in macrophages of LOX-1TG mice. Six-week-old male LOX-1TG and wild-type (WT) mice were fed a high-cholesterol diet (HCD) for 30 weeks. Increased reactive oxygen species production, impaired endothelial nitric oxide synthase activity and endothelial dysfunction were observed in LOX-1TG mice as compared with WT littermates. LOX-1 overexpression led to p38 phosphorylation, increased nuclear factor κB activity and subsequent up-regulation of vascular cell adhesion molecule-1, thereby favouring macrophage accumulation and aortic fatty streaks. Consistently, HCD-fed double-mutant LOX-1TG/ApoE(-/-) displayed oxidative stress and vascular inflammation with higher aortic plaques than ApoE(-/-) controls. Finally, bone marrow transplantation experiments showed that endothelial LOX-1 was sufficient for atherosclerosis development in vivo.
  
  
  CONCLUSIONS
  Endothelial-specific LOX-1 overexpression enhanced aortic oxLDL levels, thereby favouring endothelial dysfunction, vascular inflammation and plaque formation. Thus, LOX-1 may serve as a novel therapeutic target for atherosclerosis.
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Rozenberg
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Paneni
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Carola
authors.initials: C
authors.lastname: Doerries
authors.affiliation: Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland Neuroimmunology Unit, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Sledzinska
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Pavani
authors.initials: P
authors.lastname: Mocharla
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Breitenstein
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Lohmann
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Sokrates
authors.initials: S
authors.lastname: Stein
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: von Lukowicz
authors.affiliation: Division of Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Kurrer
authors.affiliation: Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Göteborg, Gothenburg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.affiliation: Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland Neuroimmunology Unit, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Felix C
authors.initials: FC
authors.lastname: Tanner
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland cardiotfl@gmx.ch.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism; D001013:Aorta, Thoracic / Q000378:metabolism; D001025:Aortitis / Q000209:etiology; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology*; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D058226:Plaque, Atherosclerotic / Q000209:etiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; C495138:Olr1 protein, mouse; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E
keywords: Atherosclerosis; Endothelium; Vascular inflammation