APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans.

1. Nature. 2021 Sep;597(7874):92-96. doi: 10.1038/s41586-021-03818-3. Epub 2021 Aug 25.

APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans.

Tsiantoulas D(1), Eslami M(2), Obermayer G(3)(4), Clement M(5), Smeets D(3), Mayer FJ(3), Kiss MG(3)(4), Enders L(4), Weißer J(4), Göderle L(3)(4), Lambert J(5), Frommlet F(6), Mueller A(4), Hendrikx T(3), Ozsvar-Kozma M(3)(4), Porsch F(3)(4), Willen L(2), Afonyushkin T(3)(4), Murphy JE(5), Fogelstrand P(7), Donzé O(8), Pasterkamp G(9), Hoke M(10), Kubicek S(4), Jørgensen HF(5), Danchin N(11)(12), Simon T(13)(14), Scharnagl H(15), März W(15)(16)(17), Borén J(7), Hess H(18), Mallat Z(#)(5)(19), Schneider P(#)(2), Binder CJ(20)(21).

Author information: (1)Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. dimitris.tsiantoulas@meduniwien.ac.at. (2)Department of Biochemistry, University of Lausanne, Epalinges, Switzerland. (3)Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. (4)CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. (5)Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK. (6)Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria. (7)Institute of Medicine, University of Gothenburg, Göteborg, Sweden. (8)Adipogen Life Sciences, Epalinges, Switzerland. (9)University Medical Center Utrecht, Utrecht, the Netherlands. (10)Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria. (11)Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Department of Cardiology, Paris, France. (12)University School of Medicine, Université de Paris, Paris, France. (13)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), Paris, France. (14)Department of Pharmacology, Sorbonne-Université (UPMC-Paris 06), Paris, France. (15)Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. (16)Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. (17)SYNLAB Academy, Synlab Holding Deutschland GmbH, Augsburg, Germany. (18)Translational Innovation Platform Immunology, Merck KGaA, Darmstadt, Germany. (19)Université de Paris and INSERM U970, Paris Cardiovascular Research Center, Paris, France. (20)Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. christoph.binder@meduniwien.ac.at. (21)CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. christoph.binder@meduniwien.ac.at. (#)Contributed equally

Comment in Nat Rev Drug Discov. 2021 Oct;20(10):740. doi: 10.1038/d41573-021-00152-1.

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.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

DOI: 10.1038/s41586-021-03818-3 PMID: 34433968 [Indexed for MEDLINE]