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Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo

Akhmedov, Alexander ; Rozenberg, Izabela ; Paneni, Francesco ; Camici, Giovanni G. ; Shi, Yi ; Doerries, Carola ; Sledzinska, Anna ; Mocharla, Pavani ; Breitenstein, Alexander ; Lohmann, Christine ; Stein, Sokrates ; von Lukowicz, Tobias ; Kurrer, Michael O. ; Borén, Jan ; Becher, Burkhard ; Tanner, Felix C. ; Landmesser, Ulf ; Matter, Christian M. ; Lüscher, Thomas F.

In: European Heart Journal, 2014, vol. 35, no. 40, p. 2839-2848

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    Titre
    • Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo
    Auteur
    • Akhmedov, Alexander. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Rozenberg, Izabela. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Paneni, Francesco. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Camici, Giovanni G.. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Shi, Yi. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Doerries, Carola. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Sledzinska, Anna. Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
    • Mocharla, Pavani. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Breitenstein, Alexander. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Lohmann, Christine. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Stein, Sokrates. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • von Lukowicz, Tobias. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Kurrer, Michael O.. Division of Pathology, University Hospital Zurich, Zurich, Switzerland
    • Borén, Jan. Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Göteborg, Gothenburg, Sweden
    • Becher, Burkhard. Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
    • Tanner, Felix C.. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Landmesser, Ulf. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Matter, Christian M.. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    • Lüscher, Thomas F.. Cardiovascular Research, Institute of Physiology, University of Zurich; and Cardiovascular Center, Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • European Heart Journal, 2014, vol. 35, no. 40, p. 2839-2848. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:304938
    Summary
    Aims 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. Methods and 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