APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans.

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State: Public
Version: Author's accepted manuscript
License: All rights reserved
Serval ID
serval:BIB_17F331130FAD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans.
Journal
Nature
Author(s)
Tsiantoulas D., Eslami M., Obermayer G., Clement M., Smeets D., Mayer F.J., Kiss M.G., Enders L., Weißer J., Göderle L., Lambert J., Frommlet F., Mueller A., Hendrikx T., Ozsvar-Kozma M., Porsch F., Willen L., Afonyushkin T., Murphy J.E., Fogelstrand P., Donzé O., Pasterkamp G., Hoke M., Kubicek S., Jørgensen H.F., Danchin N., Simon T., Scharnagl H., März W., Borén J., Hess H., Mallat Z., Schneider P., Binder C.J.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
25/08/2021
Peer-reviewed
Oui
Volume
597
Number
7874
Pages
92-96
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide <sup>1</sup> . The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs) <sup>2</sup> and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall <sup>2</sup> . A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs <sup>3</sup> , but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis.
Pubmed
Web of science
Create date
03/09/2021 16:56
Last modification date
23/02/2022 7:08
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