Leukocyte trafficking-associated vascular adhesion protein 1 is expressed and functionally active in atherosclerotic plaques

: Silvola JMU, Virtanen H, Siitonen R, Hellberg S, Liljenback H, Metsala O, Stahle M, Saanijoki T, Kakela M, Hakovirta H, Yla-Herttuala S, Saukko P, Jauhiainen M, Veres TZ, Jalkanen S, Knuuti J, Saraste A, Roivainen A

Publisher: NATURE PUBLISHING GROUP

: 2016

: Scientific Reports

: SCIENTIFIC REPORTS

: SCI REP-UK

: ARTN 35089

: 6

: 10

: 2045-2322

DOI: https://doi.org/10.1038/srep35089

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-/- ApoB(100/100)), 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 [Ga-68]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.

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