Inhibition of immunoproteasome promotes angiogenesis via enhancing hypoxia-inducible factor-1α abundance in rats following focal cerebral ischaemia
Inhibition of immunoproteasome promotes angiogenesis via enhancing hypoxia-inducible factor-1α abundance in rats following focal cerebral ischaemia
复制标题
免疫蛋白酶体的抑制通过增强大鼠局灶性脑缺血后缺氧诱导因子-1α的丰度来促进血管生成。
DOI：
10.1016/j.bbi.2018.04.009
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发表时间：
2018-10-01
影响因子：
15.1
通讯作者：
Wang, Yinzhou
中科院分区：
文献类型：
--
作者：
Chen, Xingyong;Zhang, Xu;Wang, Yinzhou
缺血性中风后的血管新生有助于缺血区血液供应的恢复。改善血管生成的策略可能有助于卒中后功能的恢复。越来越多的证据表明，蛋白酶体抑制剂在啮齿动物模型中促进血管神经发生并诱导脑缺血后的长期神经保护作用。我们以前曾报道，抑制免疫蛋白酶体亚单位低分子量肽2（LMP 2）提供了一个强大的缺血性中风大鼠的神经保护。然而，目前还没有数据表明免疫蛋白酶体与缺血性卒中背景下血管生成的关系。在这项研究中，我们确定，抑制免疫蛋白酶体LMP 2能够增强血管生成，促进大鼠局灶性脑缺血/再灌注后神经功能的恢复。在体外培养的星形胶质细胞中，氧糖剥夺和再灌注（OGD/R）显着增强免疫蛋白酶体LMP 2的表达和蛋白酶体活性，但这些有益的影响被取消敲低LMP 2与siRNA转染。沿着的是，在体内和体外抑制LMP 2可显著增加HIF-1 α的蛋白丰度，并与血管生成和细胞命运相关。然而，这些有益的作用被HIF-1 α抑制剂2-甲氧基乙烯基吡咯烷酮（2 ME）部分消除。合在一起;这项研究强调了抑制LMP 2在促进缺血性中风血管生成事件中的重要作用，并指出HIF-1 α是这种反应的关键介质，这表明免疫蛋白酶体抑制剂可能是治疗中风的有希望的策略。
Angiogenesis after ischemic stroke contributes to the restoration of blood supply in the ischemic zone. Strategies to improve angiogenesis may facilitate the function recovery after stroke. Growing evidence shows that proteasome inhibitors enhance angioneurogenesis and induces a long-term neuroprotection after cerebral ischemia in rodents' models. We have previously reported that inhibition of the immunoproteasome subunit low molecular mass peptide 2 (LMP2) offers a strong neuroprotection in ischemic stroke rats. However, there are no data available to show the relationship between immunoproteasome and angiogenesis under ischemia stroke context. In this study, we identified that inhibition of immunoproteasome LMP2 was able to enhance angiogenesis and facilitate neurological functional recovery in rats after focal cerebral ischemia/reperfusion. In vitro, oxygen glucose deprivation and reperfusion (OGD/R) significantly enhanced the expression of immunoproteasome LMP2 and proteasome activities in primary culture astrocytes, but these beneficial effects were abolished by knockdown of LMP2 with siRNA transfection. Along with this, protein abundance of HIF-1 alpha was significantly increased by inhibition LMP2 in vivo and in vitro and was associated with angiogenesis and cell fates. However, these beneficial effects were partly abolished by HIF-1 alpha inhibitor 2-methoxyestradiol (2ME). Taken together; this study highlights an important role for inhibition of LMP2 in promoting angiogenesis events in ischemic stroke, and point to HIF-1 alpha as a key mediator of this response, suggesting that immunoproteasome inhibitors may be a promising strategy for stroke treatment.