同时阻断 ANGPTL3 和 CD47 可通过调节脂质代谢、巨噬细胞排泄和脂质过氧化防止动脉粥样硬化的发展。

IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Xiaozhi Hu , Yanyang Nan , Yuting Zhang , Jiajun Fan , Hanqi Wang , Yu Bai , Yuanzhen Zhang , Xuyao Zhang , Zeguo Zhu , Zhonglian Cao , Xiaomiao Ye , Tao Wu , Shuwen Xu , Zhengyu Wu , Wei Hu , Dianwen Ju
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引用次数: 0

摘要

动脉粥样硬化(AS)最终会导致重大不良心血管事件(MACE)。虽然传统的降脂策略减少了心血管不良事件的发生,但许多患者仍面临巨大风险。这可能是由于AS病变中CD47表达上调,介导了巨噬细胞的抗吞噬作用。因此,我们提出同时阻断脂质代谢的重要调节因子ANGPTL3和CD47可能是治疗强直性脊柱炎的一种潜在方法。首先,我们研究了一种新型抗ANGPTL3纳米抗体-Fc(FD03)在强直性脊柱炎中的作用。我们发现,与对照Ab相比,FD03治疗可明显降低apoE-/-小鼠的循环脂质、斑块大小和脂质沉积,但斑块的形成与基线相比增加了两倍。不过,免疫荧光显示,与正常血管组织相比,即使经过 FD03 处理,斑块中 CD47 的表达也会上调。接下来,研究人员构建了一种包含信号调节蛋白α(SIRPα)和 FD03(SIRPαD1-FD03)的双功能蛋白,用于同时阻断 CD47 和 ANGPTL3,该蛋白纯度高、稳定性强,与 CD47 和 ANGPTL3 的亲和力高,在体外具有生物活性。此外,与SIRPαD1-Fc或FD03相比,SIRPαD1-FD03融合蛋白对强直性脊柱炎的治疗效果更强,可使斑块内容物和坏死核心消退至基线水平。从机理上讲,SIRPαD1-FD03能降低血清脂质,提高巨噬细胞的流出率和M2极化,降低动脉粥样硬化斑块中的活性氧(ROS)和脂质过氧化水平。总之,我们的项目提出了一种同时阻断ANGPTL3和CD47以调节脂质代谢、巨噬细胞活性和脂质过氧化的治疗强直性脊柱炎的有效方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Simultaneously blocking ANGPTL3 and CD47 prevents the progression of atherosclerosis through regulating lipid metabolism, macrophagic efferocytosis and lipid peroxidation
Atherosclerosis (AS) ultimately cause major adverse cardiovascular events (MACEs). While traditional strategies by lipid-reducing have reduced MACEs, many patients continue to face significant risks. It might attribute to the upregulation of CD47 expression in AS lesions, that mediated anti-efferocytosis of macrophages. Therefore, we propose simultaneously blocking ANGPTL3, a vital regulator of lipid metabolism, and CD47 might be a potential approach for AS therapy. Firstly, we investigate the role of a novel anti-ANGPTL3 nanobody-Fc (FD03) in AS. We found that FD03 treatment significantly decreased circulating lipids, plaque size, and lipid deposition in apoE-/- mice compared to control Ab, but there was a twofold increase in plaque formation in comparison to baseline. However, immunofluorescence indicated the upregulation of CD47 expression in the plaques even after FD03 treatment compared to normal vascular tissue. Next, a bifunctional protein containing signal regulatory protein alpha (SIRPα) and FD03 (SIRPαD1-FD03) was constructed to block CD47 and ANGPTL3 concurrently, which had high purity, robust stability, and high affinity to CD47 and ANGPTL3 with biological activity in vitro. Furthermore, SIRPαD1-FD03 fusion protein exhibited the enhanced therapeutic effect on AS compared with SIRPαD1-Fc or FD03, regressing plaque contents and the necrotic core equal to baseline. Mechanistically, SIRPαD1-FD03 reduced serum lipids, augmented the efferocytosis rate and macrophage M2 polarization, and decreased the reactive oxygen species (ROS) and lipid peroxidation level in atherosclerotic plaques. Collectively, our project suggests an effective approach for AS by simultaneously blocking ANGPTL3 and CD47 to regulate lipid metabolism, macrophage activity and lipid peroxidation.
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来源期刊
Pharmacological research
Pharmacological research 医学-药学
CiteScore
18.70
自引率
3.20%
发文量
491
审稿时长
8 days
期刊介绍: Pharmacological Research publishes cutting-edge articles in biomedical sciences to cover a broad range of topics that move the pharmacological field forward. Pharmacological research publishes articles on molecular, biochemical, translational, and clinical research (including clinical trials); it is proud of its rapid publication of accepted papers that comprises a dedicated, fast acceptance and publication track for high profile articles.
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