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SCFFBXO3 泛素 E3 连接酶调节动脉粥样硬化中的炎症反应。

The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis.

机构信息

Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.

Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States.

出版信息

J Mol Cell Cardiol. 2019 Jan;126:50-59. doi: 10.1016/j.yjmcc.2018.11.006. Epub 2018 Nov 16.

Abstract

Inflammation is critical in the pathobiology of atherosclerosis. An essential player in the inflammatory process in atherosclerosis are macrophages that scavenge oxidatively modified low-density lipoproteins (OxLDL) deposited in the subendothelium of systemic arteries that secrete a myriad of pro-inflammatory mediators. Here, we identified that a subunit of the Skp-Cullin-F-box ubiquitin E3 ligase apparatus, termed FBXO3, modulates the inflammatory response in atherosclerosis. Specifically, individuals with a hypofunctioning genetic variant of FBXO3 develop less atherosclerosis. FBXO3 protein is present in cells of monocytic lineage within carotid plaques and its levels increase in those with symptomatic compared with asymptomatic atherosclerosis. Further, cellular depletion or small molecule inhibition of FBXO3 significantly reduced the inflammatory response to OxLDL by macrophages without altering OxLDL uptake. Thus, FBXO3 potentiates vascular inflammation and atherosclerosis that can be effectively mitigated by a small molecule inhibitor.

摘要

炎症反应在动脉粥样硬化的病理生物学中起着关键作用。在动脉粥样硬化的炎症反应中,巨噬细胞是一个重要的参与者,它可以清除沉积在系统性动脉内膜下的氧化修饰的低密度脂蛋白(OxLDL),并分泌多种促炎介质。在这里,我们发现 Skp-Cullin-F-box 泛素 E3 连接酶装置的一个亚基,称为 FBXO3,可调节动脉粥样硬化中的炎症反应。具体来说,FBXO3 遗传变异功能低下的个体动脉粥样硬化的发展程度较轻。FBXO3 蛋白存在于颈动脉斑块的单核细胞谱系细胞中,并且在有症状的动脉粥样硬化患者中其水平升高,而无症状的患者中则没有。此外,细胞耗竭或 FBXO3 的小分子抑制剂可显著降低巨噬细胞对 OxLDL 的炎症反应,而不改变 OxLDL 的摄取。因此,FBXO3 增强了血管炎症和动脉粥样硬化,而小分子抑制剂可有效减轻其影响。

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N Engl J Med. 2017 Sep 21;377(12):1119-1131. doi: 10.1056/NEJMoa1707914. Epub 2017 Aug 27.
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E3 ubiquitin ligases as novel targets for inflammatory diseases.E3泛素连接酶作为炎症性疾病的新型靶点。
Pharmacol Res. 2016 Apr;106:1-9. doi: 10.1016/j.phrs.2016.02.006. Epub 2016 Feb 11.
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Novel anti-inflammatory therapies for the treatment of atherosclerosis.新型抗炎疗法治疗动脉粥样硬化。
Atherosclerosis. 2015 Jun;240(2):497-509. doi: 10.1016/j.atherosclerosis.2015.04.783. Epub 2015 Apr 18.
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Anti-inflammatory therapies for atherosclerosis.抗动脉粥样硬化炎症治疗。
Nat Rev Cardiol. 2015 Apr;12(4):199-211. doi: 10.1038/nrcardio.2015.5. Epub 2015 Feb 10.

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