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Brain Behav Immun. 2018 Oct;73:167-179. doi: 10.1016/j.bbi.2018.04.009. Epub 2018 Apr 18.

Inhibition of immunoproteasome promotes angiogenesis via enhancing hypoxia-inducible factor-1α abundance in rats following focal cerebral ischaemia.

Author information

1
Department of Neurology, Fujian Provincial Hospital, Fujian Medical University Shengli Clinical College, Fuzhou 350001, PR China. Electronic address: cxyong77@163.com.
2
Department of Neurology, Fujian Provincial Hospital, Fujian Medical University Shengli Clinical College, Fuzhou 350001, PR China. Electronic address: zhangxufjsl@163.com.
3
Department of Neurology, Fujian Provincial Hospital, Fujian Medical University Shengli Clinical College, Fuzhou 350001, PR China. Electronic address: ct717@163.com.
4
Department of Neurology, Fujian Provincial Hospital, Fujian Medical University Shengli Clinical College, Fuzhou 350001, PR China. Electronic address: jiangxiulong2@yeah.net.
5
Department of Neurology, Fujian Provincial Hospital, Fujian Medical University Shengli Clinical College, Fuzhou 350001, PR China. Electronic address: nestinkangti@163.com.
6
Department of Neurology, Fujian Provincial Hospital, Fujian Medical University Shengli Clinical College, Fuzhou 350001, PR China. Electronic address: lhx.d@163.com.
7
Department of Neurology, Fujian Provincial Hospital, Fujian Medical University Shengli Clinical College, Fuzhou 350001, PR China. Electronic address: wphd@163.com.

Abstract

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-1α 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-1α 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-1α as a key mediator of this response, suggesting that immunoproteasome inhibitors may be a promising strategy for stroke treatment.

KEYWORDS:

Angiogenesis; Hypoxia-inducible factor-1a; Immunoproteasome; Ischemic stroke

PMID:
29679638
DOI:
10.1016/j.bbi.2018.04.009
[Indexed for MEDLINE]

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