Inhibition of neddylation by MLN4924 improves neointimal hyperplasia and promotes apoptosis of vascular smooth muscle cells through p53 and p62
Inhibition of neddylation by MLN4924 improves neointimal hyperplasia and promotes apoptosis of vascular smooth muscle cells through p53 and p62
复制标题
MLN4924 抑制 neddylation 可改善内膜增生，并通过 p53 和 p62 促进血管平滑肌细胞凋亡
DOI：
10.1038/cdd.2017.160
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发表时间：
2018-02-01
影响因子：
12.4
通讯作者：
Duan, Sheng-Zhong
中科院分区：
文献类型：
--
作者：
Ai, Tang-Jun;Sun, Jian-Yong;Duan, Sheng-Zhong
靶向血管平滑肌细胞（VSMCs）凋亡是减少再狭窄发生的一种有吸引力的方法。类化修饰是一个高度保守的翻译后修饰过程，抑制类化修饰可调节其他细胞的凋亡。然而，类化抑制对VSMCs和新生内膜增生的影响尚未得到研究。在本研究中，我们发现nedd8活化酶（NAE）的选择性抑制剂MLN4924可以显著抑制血管内膜增生和VSMCs的积累，同时增加血管壁的凋亡。体外研究表明，MLN4924可诱导人VSMCs的G2/M阻滞和凋亡。NAE1的敲低也有类似的效果。MLN4924上调人VSMCs中的p53和p62。敲低p53或p62均可减轻MLN4924对G2/M阻滞和细胞凋亡的影响。此外，p53敲除可消除mln4924诱导的p62上调。最后，生成平滑肌p53敲除小鼠，进行股动脉损伤和MLN4924处理。平滑肌中p53缺失可阻断MLN4924对内膜增生和细胞凋亡的影响。综上所述，我们的研究结果表明，类化抑制通过p53和p62诱导小鼠VSMCs细胞凋亡，并主要通过平滑肌p53促进细胞凋亡来改善小鼠内膜增生。这些临床前数据为使用MLN4924干扰类化修饰靶向再狭窄提供了强有力的翻译意义。
Targeting apoptosis of vascular smooth muscle cells (VSMCs) represents an attractive approach to diminish the occurrence of restenosis. Neddylation is a highly conserved post-translational modification process and inhibition of neddylation has been shown to regulate apoptosis of other cells. However, the impacts of neddylation inhibition on VSMCs and neointimal hyperplasia have not been studied. In our present study, we have shown that MLN4924, a selective inhibitor of NEDD8-activating enzyme (NAE), markedly inhibited neointimal hyperplasia and accumulation of VSMCs, whereas increased apoptosis in the vascular wall. In vitro studies revealed that MLN4924 induced G2/M arrest and apoptosis of human VSMCs. Knockdown of NAE1 had similar effects. MLN4924 upregulated p53 and p62 in human VSMCs. Knockdown of either p53 or p62 mitigated the impacts of MLN4924 on G2/M arrest and apoptosis. Moreover, p53 knockdown abolished MLN4924-induced upregulation of p62. Finally, smooth muscle p53 knockout mice were generated and subjected to femoral artery injury and MLN4924 treatment. Deficiency of p53 in smooth muscle blocked the effects of MLN4924 on neointimal hyperplasia and apoptosis. Together, our results revealed that neddylation inhibition induces apoptosis through p53 and p62 in VSMCs and improves neointimal hyperplasia mainly by promoting apoptosis through smooth muscle p53 in mice. These pre-clinical data provide strong translational implications for targeting restenosis by perturbation of neddylation using MLN4924.