Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo
Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo
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DOI：
10.1073/pnas.1618411114
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发表时间：
2017-03-28
影响因子：
11.1
通讯作者：
Bernhagen, Juergen
中科院分区：
文献类型：
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作者：
Asare, Yaw;Ommer, Miriam;Bernhagen, Juergen
组成型光形态发生9（COP 9）信号体5（CSN 5）是一种从cullin中去除神经前体细胞表达的发育下调的8（NEDD 8）部分的异肽酶（因此称为“去NEDD酶”），是cullin-RING E3连接酶调节COP 9信号体复合物的亚基，可减弱促炎性NF-κ B信号传导。我们先前表明，CSN 5在人类动脉粥样硬化动脉中上调。在这里，我们通过使用骨髓特异性Csn 5缺失的小鼠来研究CSN 5在体内动脉粥样硬化形成中的作用。在Apoe（-/-）小鼠中Csn 5基因缺失显著加剧了动脉粥样硬化病变的形成。这在雄性小鼠的主动脉根、弓和总主动脉中广泛观察到，而在雌性小鼠中的影响不太明显且不具有部位特异性。在机制上，Csn 5 KO增强了巨噬细胞中NF-κ B信号传导和促炎细胞因子表达，而HIF-1 α水平降低。相反，MLN 4924对NEDD化的抑制作用阻断了促炎基因表达和NF-κ B活化，同时增强了炎症诱导的巨噬细胞中HIF-1 α水平和M2标志物精氨酸酶1的表达。MLN 4924进一步减弱内皮细胞中趋化因子和粘附分子的表达，并降低体外活化内皮上的NF-κ B活化和单核细胞阻滞。在体内，MLN 4924可减少LPS诱导的炎症，有利于巨噬细胞表型，并减缓小鼠早期动脉粥样硬化病变的进展。相反，MLN 4924治疗增加了血液中的中性粒细胞和单核细胞计数，对更晚期病变的进展无净效应。我们的数据显示CSN 5具有动脉粥样硬化保护作用。我们得出结论，MLN 4924可能有助于预防早期动脉粥样硬化形成，而选择性促进CSN 5介导的去NEDD化可能在动脉粥样硬化的所有阶段都有益。
Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell-expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed "deNEDDylase") and a subunit of the cullin-RING E3 ligase-regulating COP9 signalosome complex, attenuates proinflammatory NF-kappa B signaling. We previously showed that CSN5 is up-regulated in human atherosclerotic arteries. Here, we investigated the role of CSN5 in atherogenesis in vivo by using mice with myeloid-specific Csn5 deletion. Genetic deletion of Csn5 in Apoe(-/-) mice markedly exacerbated atherosclerotic lesion formation. This was broadly observed in aortic root, arch, and total aorta of male mice, whereas the effect was less pronounced and site-specific in females. Mechanistically, Csn5 KO potentiated NF-kappa B signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1 alpha levels were reduced. Inversely, inhibition of NEDDylation by MLN4924 blocked proinflammatory gene expression and NF-kappa B activation while enhancing HIF-1 alpha levels and the expression of M2 marker Arginase 1 in inflammatory-elicited macrophages. MLN4924 further attenuated the expression of chemokines and adhesion molecules in endothelial cells and reduced NF-kappa B activation and monocyte arrest on activated endothelium in vitro. In vivo, MLN4924 reduced LPS-induced inflammation, favored an antiinflammatory macrophage phenotype, and decreased the progression of early atherosclerotic lesions in mice. On the contrary, MLN4924 treatment increased neutrophil and monocyte counts in blood and had no net effect on the progression of more advanced lesions. Our data show that CSN5 is atheroprotective. We conclude that MLN4924 may be useful in preventing early atherogenesis, whereas selectively promoting CSN5-mediated deNEDDylation may be beneficial in all stages of atherosclerosis.