title: Endothelial LOX-1 activation differentially regulates arterial thrombus formation depending on oxLDL levels: role of the Oct-1/SIRT1 and ERK1/2 pathways.
abstract: OBJECTIVE
  The lectin-like oxLDL receptor-1 (LOX-1) promotes endothelial uptake of oxidized low-density lipoprotein (oxLDL) and plays an important role in atherosclerosis and acute coronary syndromes (ACS). However, its role in arterial thrombus formation remains unknown. We investigated whether LOX-1 plays a role in arterial thrombus formation in vivo at different levels of oxLDL using endothelial-specific LOX-1 transgenic mice (LOX-1TG) and a photochemical injury thrombosis model of the carotid artery.
  
  
  RESULTS
  In mice fed a normal chow diet, time to arterial occlusion was unexpectedly prolonged in LOX-1TG as compared to WT. In line with this, tissue factor (TF) expression and activity in carotid arteries of LOX-1TG mice were reduced by half. This effect was mediated by activation of octamer transcription factor 1 (Oct-1) leading to upregulation of the mammalian deacetylase silent information regulator-two 1 (SIRT1) via binding to its promoter and subsequent inhibition of NF-κB signaling. In contrast, intravenous injection of oxLDL as well as high cholesterol diet for 6 weeks led to a switch from the Oct-1/SIRT1 signal transduction pathway to the ERK1/2 pathway and in turn to an enhanced thrombotic response with shortened occlusion time.
  
  
  CONCLUSIONS
  Thus, LOX-1 differentially regulates thrombus formation in vivo depending on the degree of activation by oxLDL. At low oxLDL levels LOX-1 activates the protective Oct-1/SIRT1 pathway, while at higher levels of the lipoprotein switches to the thrombogenic ERK1/2 pathway. These findings may be important for arterial thrombus formation in ACS and suggest that SIRT1 may represent a novel therapeutic target in this context.
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Division of Internal Medicine, Cantonal Hospital Baden, Im Ergel 1, CH-5404 Baden, Switzerland.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Reiner
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Bonetti
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Cardiology Unit, Department of Medicine, Karolinska University Hospital, Karolinska vägen, 171 76 Solna, Stockholm, Sweden.
authors.forename: Sarah
authors.initials: S
authors.lastname: Costantino
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Erik W
authors.initials: EW
authors.lastname: Holy
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Remo D
authors.initials: RD
authors.lastname: Spescha
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Division of Internal Medicine, Cantonal Hospital Baden, Im Ergel 1, CH-5404 Baden, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Stivala
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Ariane
authors.initials: A
authors.lastname: Schaub Clerigué
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Internal Medicine 4, Saarland University Hospital, Kirrberger Str. 100, D-66424 Homburg, Saarland, Germany.
authors.forename: Thimoteus
authors.initials: T
authors.lastname: Speer
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Breitenstein
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Manz
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Lohmann
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Cardiology Unit, Department of Medicine, Karolinska University Hospital, Karolinska vägen, 171 76 Solna, Stockholm, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Paneni
authors.affiliation: Division of Internal Medicine, Cantonal Hospital Baden, Im Ergel 1, CH-5404 Baden, Switzerland.
authors.forename: Juerg-Hans
authors.initials: JH
authors.lastname: Beer
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.|Department of Cardiology, University Heart Centre, University Hospital Zurich, Rämistr. 100, CH-8091 Zurich, Switzerland.|Zurich Center of Integrative Human Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D000818:Animals; D001665:Binding Sites; D001777:Blood Coagulation; D002339:Carotid Arteries / Q000201:enzymology*; D020212:Carotid Artery Injuries / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D013997:Time Factors
chemical_list: D002791:Cholesterol, Dietary; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D050811:Octamer Transcription Factor-1; C495138:Olr1 protein, mouse; C494166:Pou2f1 protein, mouse; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D013925:Thromboplastin; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: LOX-1 • Arterial thrombosis • Endothelium • Tissue factor