APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans
Tsiantoulas, Dimitrios; Eslami, Mahya; Obermayer, Georg; Clement, Marc; Smeets, Diede; Mayer, Florian J; Kiss, Máté G; Enders, Lennart; Weißer, Juliane; Göderle, Laura; Lambert, Jordi; Frommlet, Florian; Mueller, André; Hendrikx, Tim; Ozsvar-Kozma, Maria; Porsch, Florentina; Willen, Laure; Afonyushkin, Taras; Murphy, Jane E; Fogelstrand, Per; Donzé, Olivier; Pasterkamp, Gerard; Hoke, Matthias; Kubicek, Stefan; Jørgensen, Helle F; Danchin, Nicolas; Simon, Tabassome; Scharnagl, Hubert; März, Winfried; Borén, Jan; Hess, Henry; Mallat, Ziad; Schneider, Pascal; Binder, Christoph J
(2021) Nature, volume 597, issue 7874, pp. 92 - 96
(Article)
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
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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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Keywords: General, Journal Article
ISSN: 0028-0836
Publisher: Nature Publishing Group
Note: Funding Information: Extended Data Fig. 3 | APRIL is produced by mouse and human VSMCs. a, TNFSF13 gene expression in human tissues in the Genotype-Tissue Expression (GTEx) project36. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data described in this manuscript were obtained from the GTEx Portal on 21 January 2021 and dbGaP accession number phs000424.v8.p2. The results show median (aorta: median = 55.05, n = 432; coronary artery: median = 40.7, n = 240). b, c, Bulk RNA-seq analysis of VSMCs from the aortic arch (AA) and descending thoracic aorta (DT) (b; n = 3–5 mice) (GSE117963) and from mouse primary VSMCs that were stored in Trizol after isolation or had been cultured for 4–5 passages until the analysis (c; GSE17858). TNFSF13, MYH11 and KI67 gene expression are depicted. d, TNFSF13 and IL6 gene expression by human umbilical artery smooth muscle cells that were stimulated in quadruplicate with recombinant human TNF, native human LDL or human oxLDL (TNF stimulation is representative of three independent experiments; P = 0.003). Results show mean ± s.e.m. **P < 0.01 (one-way ANOVA and Tukey’s test). Funding Information: Acknowledgements We thank A. Fabry and T. Wenko for help with the in vivo experimental studies, and C. Friedl for help with confocal microscopy. This work was supported by grants from the Austrian Science Fund (SFB F54), the European Union (FP7 VIA) and the Leducq Foundation (TNE-20CVD03) to C.J.B., and by grants from the European Research Area Network on Cardiovascular Diseases (I4647) and the British Heart Foundation (RCAG/917) to D.T. D.T. is also supported by the Austrian Science Fund (I4963). P.S. is supported by the Swiss National Science Foundation (31003A_176256, 310030E_197000). Z.M. is supported by the British Heart Foundation (RCAM/104, RCAM-659, RRCAM.163), the British Heart Foundation Center for Research Excellence (RE/18/1/34212), the NIHR Cambridge Biomedical Research Centre (RG85315), the European Union (FP7 VIA; RCAG/430) and the European Research Council (ERC). T.H. is supported by a NWO Veni grant (91619012). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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