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APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide1. The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs)2 and become trapped in the subendothelial s...

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Main Authors: Tsiantoulas, Dimitrios (Author) , Eslami, Mahya (Author) , Obermayer, Georg (Author) , Clement, Marc (Author) , Smeets, Diede (Author) , Mayer, Florian J. (Author) , Kiss, Máté G. (Author) , Enders, Lennart (Author) , Weißer, Juliane (Author) , Göderle, Laura (Author) , Lambert, Jordi (Author) , Frommlet, Florian (Author) , Mueller, André (Author) , Hendrikx, Tim (Author) , Ozsvar-Kozma, Maria (Author) , Porsch, Florentina (Author) , Willen, Laure (Author) , Afonyushkin, Taras (Author) , Murphy, Jane E. (Author) , Fogelstrand, Per (Author) , Donzé, Olivier (Author) , Pasterkamp, Gerard (Author) , Hoke, Matthias (Author) , Kubicek, Stefan (Author) , Jørgensen, Helle F. (Author) , Danchin, Nicolas (Author) , Simon, Tabassome (Author) , Scharnagl, Hubert (Author) , März, Winfried (Author) , Borén, Jan (Author) , Hess, Henry (Author) , Mallat, Ziad (Author) , Schneider, Pascal (Author) , Binder, Christoph J. (Author)
Format: Article (Journal)
Language:English
Published: 25 August 2021
In: Nature
Year: 2021, Volume: 597, Pages: 92-96
ISSN:1476-4687
DOI:10.1038/s41586-021-03818-3
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41586-021-03818-3
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41586-021-03818-3
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Author Notes:Dimitrios Tsiantoulas, Mahya Eslami, Georg Obermayer, Marc Clement, Diede Smeets, Florian J. Mayer, Máté G. Kiss, Lennart Enders, Juliane Weißer, Laura Göderle, Jordi Lambert, Florian Frommlet, André Mueller, Tim Hendrikx, Maria Ozsvar-Kozma, Florentina Porsch, Laure Willen, Taras Afonyushkin, Jane E. Murphy, Per Fogelstrand, Olivier Donzé, Gerard Pasterkamp, Matthias Hoke, Stefan Kubicek, Helle F. Jørgensen, Nicolas Danchin, Tabassome Simon, Hubert Scharnagl, Winfried März, Jan Borén, Henry Hess, Ziad Mallat, Pascal Schneider and Christoph J. Binder

MARC

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520 |a Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide1. The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs)2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall2. A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs3, 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. 
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