奥地利维也纳医科大学Christoph J. Binder、Dimitrios Tsiantoulas等研究人员合作发现，APRIL通过与硫酸肝素蛋白多糖结合限制动脉粥样硬化。相关论文于2021年8月25日在线发表在《自然》杂志上。
研究人员表示，动脉粥样硬化性心血管疾病导致心脏病发作和中风，这是全世界死亡的主要原因。当低密度脂蛋白与肝素-硫酸酯蛋白多糖（HSPG）结合并被困在大、中型动脉的内皮下空间时，动脉粥样硬化斑块开始形成，这导致了慢性炎症和动脉壁的重塑。增殖诱导配体（APRIL）是一种能与HSPG结合的细胞因子，但这种相互作用的生理学在很大程度上是未知的。
研究人员发现，APRIL的基因敲除或抗体介导的耗竭会加重小鼠的动脉粥样硬化。在机制上，研究人员证明APRIL通过与硫酸肝素蛋白多糖2（HSPG2）的硫酸肝素链结合，限制了低密度脂蛋白的滞留、巨噬细胞的聚集和坏死核心的形成，从而赋予动脉粥样硬化保护。事实上，在表达肝素硫酸盐缺陷型HSPG2的小鼠中，抗体介导的APRIL耗竭对动脉粥样硬化的发展没有影响。用一种促进APRIL与HSPG结合的特异性抗APRIL抗体治疗可减少实验性动脉粥样硬化。此外，一种与HSPG结合的人类APRIL蛋白的血清水平，研究人员称之为非经典APRIL（nc-APRIL），与动脉粥样硬化患者的长期心血管死亡有关，且不依赖于与传统的风险因素。这些数据揭示了APRIL的特性，对血管稳态有广泛的病理生理学影响。
附：英文原文
Title: APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans
Author: Tsiantoulas, Dimitrios, Eslami, Mahya, Obermayer, Georg, Clement, Marc, Smeets, Diede, Mayer, Florian J., Kiss, Mt G., Enders, Lennart, Weier, Juliane, Gderle, Laura, Lambert, Jordi, Frommlet, Florian, Mueller, Andr, Hendrikx, Tim, Ozsvar-Kozma, Maria, Porsch, Florentina, Willen, Laure, Afonyushkin, Taras, Murphy, Jane E., Fogelstrand, Per, Donz, Olivier, Pasterkamp, Gerard, Hoke, Matthias, Kubicek, Stefan, Jrgensen, Helle F., Danchin, Nicolas, Simon, Tabassome, Scharnagl, Hubert, Mrz, Winfried, Born, Jan, Hess, Henry, Mallat, Ziad, Schneider, Pascal, Binder, Christoph J.
Issue&Volume: 2021-08-25
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.
DOI: 10.1038/s41586-021-03818-3
Source: https://www.nature.com/articles/s41586-021-03818-3
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
