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.

Exploring the radiosynthesis and in vitro characteristics of [68Ga]Ga‐DOTA‐Siglec‐9

“…Our intention is to use a Siglec‐9‐based tracer to visualize leukocyte extravasation. VAP‐1 has for several years been investigated as a potential target for in vivo imaging of inflammation via PET . The first publication dealing with VAP‐1 imaging dates back to 2000, and it described how an anti‐human‐VAP‐1 monoclonal antibody 1B2 was labelled with 123 I and evaluated in an animal model using single‐photon emission computed tomography.…”

“…Siglec‐9 has also been labelled with 5‐deoxy‐5‐[ 18 F]fluororibose (5‐deoxy‐5‐[ 18 F]fluororibose‐Siglec‐9), which is abbreviated as [ 18 F]FDR‐Siglec‐9 . [ 68 Ga]Ga‐DOTA‐Siglec‐9 has previously been evaluated in several experimental models, e.g., acute respiratory distress syndrome (ARDS), peri‐implant tissue responses, staphylococcal infections, synovitis, and atherosclerosis, and the results have been promising.…”

“…VAP-1 has for several years been investigated as a potential target for in vivo imaging of inflammation via PET. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] The first publication dealing with VAP-1 imaging dates back to 2000, and it described how an anti-human-VAP-1 monoclonal antibody 1B2 was labelled with 123 I and evaluated in an animal model using single-photon emission computed tomography. The study showed that inflammation can be visualized and that the uptake was specific compared with a simultaneously injected nonspecific antibody.…”

Monitoring inflammation injuries in the progression of atherosclerosis with contrast enhanced ultrasound molecular imaging

“…It has been widely accepted that atherosclerosis is a chronic inflammatory disease and inflammatory response plays a critical role in the initiation, progression and rupture of the atherosclerotic plaques [ 1 – 4 ]. In recent years, many noninvasive imaging modalities, including ultrasound, magnetic resonance imaging (MRI) and positron emission tomography (PET) were developed to prepare new targeted contrast agents to visualize inflammation process in atherosclerosis [ 10 – 11 , 16 – 17 ]. Compared to the other imaging modalities, ultrasound is often set to be the first choice in vascular imaging because it is noninvasive and convenient.…”

Visualisierung molekularer Zielstrukturen bei Entzündungen und Infektionen

“…Bisher konnte in wenigen präklinischen Studien das Potenzial der Immunglobuline als Targets gezeigt werden. Neben iodierten Antikörpern gegen VCAM-1 wurden 123 I-iodierte Peptide, 111 In-markierte und 18 F-fluorierte Peptide eingesetzt [19,39,40,56,101,121,127]. Untersuchungen der ICAM-1-Exression wurden mit 111 In-und 123 I-markierten anti-ICAM-1-Antikörpern durchgeführt [127].…”