APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans

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 ()
Additional contact information
Dimitrios Tsiantoulas: Medical University of Vienna
Mahya Eslami: University of Lausanne
Georg Obermayer: Medical University of Vienna
Marc Clement: University of Cambridge
Diede Smeets: Medical University of Vienna
Florian J. Mayer: Medical University of Vienna
Máté G. Kiss: Medical University of Vienna
Lennart Enders: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Juliane Weißer: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Laura Göderle: Medical University of Vienna
Jordi Lambert: University of Cambridge
Florian Frommlet: Medical University of Vienna
André Mueller: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Tim Hendrikx: Medical University of Vienna
Maria Ozsvar-Kozma: Medical University of Vienna
Florentina Porsch: Medical University of Vienna
Laure Willen: University of Lausanne
Taras Afonyushkin: Medical University of Vienna
Jane E. Murphy: University of Cambridge
Per Fogelstrand: University of Gothenburg
Olivier Donzé: Adipogen Life Sciences
Gerard Pasterkamp: University Medical Center Utrecht
Matthias Hoke: Medical University of Vienna
Stefan Kubicek: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Helle F. Jørgensen: University of Cambridge
Nicolas Danchin: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Department of Cardiology
Tabassome Simon: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint Antoine, Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRB-CRC)
Hubert Scharnagl: Medical University of Graz
Winfried März: Medical University of Graz
Jan Borén: University of Gothenburg
Henry Hess: Merck KGaA
Ziad Mallat: University of Cambridge
Pascal Schneider: University of Lausanne
Christoph J. Binder: Medical University of Vienna

Nature, 2021, vol. 597, issue 7874, 92-96

Abstract: Abstract 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-03818-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:597:y:2021:i:7874:d:10.1038_s41586-021-03818-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-03818-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().