APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans.
Details
Download: Tsiantoulas et al.pdf (3782.37 [Ko])
State: Public
Version: Author's accepted manuscript
License: All rights reserved
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
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
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