Journal Article

APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans

Mayer, Florian J., Simon, Tabassome, Donzé, Olivier, Kubicek, Stefan, Scharnagl, Hubert, Hoke, Matthias, Binder, Christoph J., Eslami, Mahya, Porsch, Florentina, Ozsvar-Kozma, Maria, Frommlet, Florian, Mallat, Ziad, Weißer, Juliane, März, Winfried, Hendrikx, Tim, Fogelstrand, Per, Willen, Laure, Afonyushkin, Taras, Hess, Henry, Jørgensen, Helle F., Borén, Jan, Obermayer, Georg, Smeets, Diede, Enders, Lennart, Danchin, Nicolas, Kiss, Máté G., Pasterkamp, Gerard, Mueller, André, Tsiantoulas, Dimitrios, Murphy, Jane E., Schneider, Pascal, Lambert, Jordi, Göderle, Laura, Clement, Marc

2021

Overview

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide 1 . 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 wall 2 . A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs 3 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/21 / 13/51 / 38/77 / 38/91 / 631/250/127 / 64/60 / 692/699/75 / 82/103 / 82/29 / 82/80 / 82/81 / Ablation / activation / Animals / Antibodies / Apolipoproteins / APRIL protein / Arteries / Arteriosclerosis / Atherosclerosis / Atherosclerosis - metabolism / Atherosclerosis - prevention & control / B-Cell Maturation Antigen - metabolism / Binding / Binding Sites / Cardiology and Cardiovascular Disease / Cardiovascular disease / Cardiovascular diseases / Cardiovascular Diseases - blood / Cardiovascular Diseases - mortality / cells / Cholesterol / Cloning / Coronary artery disease / Coronary vessels / Cytokines / Density / Depletion / Female / Gene expression / Heart diseases / Heparan sulfate / Heparan sulfate proteoglycans / Heparan Sulfate Proteoglycans - metabolism / Homeostasis / Humanities and Social Sciences / Humans / Immunoglobulins / Kardiologi och kardiovaskulära sjukdomar / Ligands / Lipoproteins / Macrophages / Male / Mice / Mice, Inbred C57BL / Mortality / multidisciplinary / perlecan / Plaques / Plasma / Protein Binding / Proteins / Proteoglycans / Retention / Risk analysis / Risk factors / roles / sample preparation / Science / Science & Technology - Other Topics / Science (multidisciplinary) / Serum levels / Smooth muscle / Sulfates / taci / Transmembrane Activator and CAML Interactor Protein - metabolism / Tumor Necrosis Factor Ligand Superfamily Member 13 - blood / Tumor Necrosis Factor Ligand Superfamily Member 13 - deficiency / Tumor Necrosis Factor Ligand Superfamily Member 13 - metabolism