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SHR Neuro Cancer Cardio Lipid Metab Microb

Tsiantoulas, D; Eslami, M; Obermayer, G; Clement, M; Smeets, D; Mayer, FJ; Kiss, MG; Enders, L; Weißer, J; Göderle, L; Lambert, J; Frommlet, F; Mueller, A; Hendrikx, T; Ozsvar-Kozma, M; Porsch, F; Willen, L; Afonyushkin, T; Murphy, JE; Fogelstrand, P; Donzé, O; Pasterkamp, G; Hoke, M; Kubicek, S; Jørgensen, HF; Danchin, N; Simon, T; Scharnagl, H; März, W; Borén, J; Hess, H; Mallat, Z; Schneider, P; Binder, CJ.
APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans.
Nature. 2021; 597(7874):92-96 Doi: 10.1038/s41586-021-03818-3
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Co-authors Med Uni Graz: März Winfried; Scharnagl Hubert
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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 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.