APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans
| Autor: | Dimitrios Tsiantoulas, Jordi Lambert, Florian J. Mayer, Winfried März, Laure Willen, Lennart Enders, Juliane Weißer, Laura Göderle, Marc Clement, Florentina Porsch, Jan Borén, Georg Obermayer, M. Kiss, Stefan Kubicek, Jane E. Murphy, Ziad Mallat, Gerard Pasterkamp, Per Fogelstrand, Florian Frommlet, Hubert Scharnagl, Tabassome Simon, Tim Hendrikx, Henry Hess, Diede Smeets, Maria Ozsvar-Kozma, Nicolas Danchin, Matthias Hoke, André C. Mueller, Olivier Donzé, Helle F. Jørgensen, Mahya Eslami, Pascal Schneider, Christoph J. Binder, Taras Afonyushkin |
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| Přispěvatelé: | Tsiantoulas, Dimitrios [0000-0002-7743-3192], Kiss, Máté G [0000-0002-9215-8328], Enders, Lennart [0000-0001-8341-3350], Göderle, Laura [0000-0003-1037-3137], Porsch, Florentina [0000-0002-2633-6632], Murphy, Jane E [0000-0003-2201-9469], Kubicek, Stefan [0000-0003-0855-8343], Jørgensen, Helle F [0000-0002-7909-2977], Borén, Jan [0000-0003-0786-8091], Mallat, Ziad [0000-0003-0443-7878], Schneider, Pascal [0000-0003-0677-9409], Binder, Christoph J [0000-0001-8313-7050], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_treatment Transmembrane Activator and CAML Interactor Protein Tumor Necrosis Factor Ligand Superfamily Member 13 Inflammation Plasma protein binding chemistry.chemical_compound Mice medicine Animals Humans B-Cell Maturation Antigen Multidisciplinary Binding Sites biology Heparan sulfate Ligand (biochemistry) Atherosclerosis Pathophysiology carbohydrates (lipids) Mice Inbred C57BL Cytokine chemistry Cardiovascular Diseases biology.protein Cancer research Female Antibody medicine.symptom Heparan Sulfate Proteoglycans Protein Binding |
| Zdroj: | Nature, vol. 597, no. 7874, pp. 92-96 |
| ISSN: | 1476-4687 |
| Popis: | 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. The heparan sulfate proteoglycan-binding cytokine APRIL has a protective role against atherosclerotic disease. |
| Databáze: | OpenAIRE |
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