title: Leukocyte trafficking-associated vascular adhesion protein 1 is expressed and functionally active in atherosclerotic plaques.
abstract: Given the important role of inflammation and the potential association of the leukocyte trafficking-associated adhesion molecule vascular adhesion protein 1 (VAP-1) with atherosclerosis, this study examined whether functional VAP-1 is expressed in atherosclerotic lesions and, if so, whether it could be targeted by positron emission tomography (PET). First, immunohistochemistry revealed that VAP-1 localized to endothelial cells of intra-plaque neovessels in human carotid endarterectomy samples from patients with recent ischemic symptoms. In low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 (LDLR-/-ApoB100/100), VAP-1 was expressed on endothelial cells lining inflamed atherosclerotic lesions; normal vessel walls in aortas of C57BL/6N control mice were VAP-1-negative. Second, we discovered that the focal uptake of VAP-1 targeting sialic acid-binding immunoglobulin-like lectin 9 based PET tracer [68Ga]DOTA-Siglec-9 in atherosclerotic plaques was associated with the density of activated macrophages (r = 0.58, P = 0.022). As a final point, we found that the inhibition of VAP-1 activity with small molecule LJP1586 decreased the density of macrophages in inflamed atherosclerotic plaques in mice. Our results suggest for the first time VAP-1 as a potential imaging target for inflamed atherosclerotic plaques, and corroborate VAP-1 inhibition as a therapeutic approach in the treatment of atherosclerosis.
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.
authors.forename: Johanna M U
authors.initials: JM
authors.lastname: Silvola
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.|Turku PET Centre, Turku University Hospital, FI-20521 Turku, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Virtanen
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Siitonen
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Hellberg
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.|Turku Center for Disease Modeling, University of Turku, FI-20520 Turku, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Liljenbäck
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Metsälä
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.
authors.forename: Mia
authors.initials: M
authors.lastname: Ståhle
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Saanijoki
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.
authors.forename: Meeri
authors.initials: M
authors.lastname: Käkelä
authors.affiliation: Department of Vascular Surgery, Turku University Hospital and University of Turku, FI-20520 Turku, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Hakovirta
authors.affiliation: A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.affiliation: Department of Pathology and Forensic Medicine, University of Turku, FI-20520 Turku, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Saukko
authors.affiliation: National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum, FI-00251 Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, FI-20520 Turku, Finland.
authors.forename: Tibor Z
authors.initials: TZ
authors.lastname: Veres
authors.affiliation: MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, FI-20520 Turku, Finland.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.|Turku PET Centre, Turku University Hospital, FI-20521 Turku, Finland.
authors.forename: Juhani
authors.initials: J
authors.lastname: Knuuti
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.|Turku PET Centre, Turku University Hospital, FI-20521 Turku, Finland.|Heart Center, Turku University Hospital, FI-20520 Turku, Finland.|Institute of Clinical Medicine, University of Turku, FI-20520 Turku, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Saraste
authors.affiliation: Turku PET Centre, University of Turku, FI-20521 Turku, Finland.|Turku PET Centre, Turku University Hospital, FI-20521 Turku, Finland.|Turku Center for Disease Modeling, University of Turku, FI-20520 Turku, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Roivainen
mesh_terms: D000328:Adult; D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D053299:Apolipoprotein B-100 / Q000378:metabolism; D016893:Carotid Stenosis / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D005260:Female; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D000072078:Positron Emission Tomography Computed Tomography; D011869:Radioligand Assay; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D053299:Apolipoprotein B-100; D015815:Cell Adhesion Molecules; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D011973:Receptors, LDL; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C000611707:siglec-9 protein, mouse; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse