Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein

被引：13

作者：

Zhang, Yuan ^{[1
,2
,3
]}

Yang, Ke ^{[1
,2
]}

Wang, Ting ^{[1
,2
]}

Li, Weiping ^{[4
]}

Jin, Xinchun ^{[5
,6
,7
]}

Liu, Wenlan ^{[1
,2
,4
]}

机构：

[1] Guangzhou Med Univ, Grad Sch, Shenzhen Peoples Hosp 2, Cent Lab, Shenzhen, Peoples R China

[2] Guangzhou Med Univ, Grad Sch, Shenzhen Peoples Hosp 2, Shenzhen Key Lab Neurosurg, Shenzhen, Peoples R China

[3] Baotou Med Coll, Dept Pathophysiol, Baotou, Peoples R China

[4] Shenzhen Univ, Shenzhen Peoples Hosp 2, Affiliated Hosp 1, Dept Neurosurg, Shenzhen, Peoples R China

[5] Soochow Univ, Affiliated Hosp 2, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Suzhou, Peoples R China

[6] Soochow Univ, Affiliated Hosp 2, Inst Neurosci, Suzhou, Peoples R China

[7] Yantai Univ, Minist Educ, Sch Pharm, Key Lab Mol Pharmacol & Drug Evaluat, Yantai, Peoples R China

来源：

FRONTIERS IN CELLULAR NEUROSCIENCE | 2017年 / 11卷

基金：

中国国家自然科学基金;

关键词：

ischemic stroke; neuronal injury; Nrdp1; apoptosis; HIF-1; alpha; USP8; UBIQUITIN-PROTEASOME SYSTEM; BRAIN-BARRIER DAMAGE; OCCLUDIN DEGRADATION; REPERFUSION INJURY; LIGASE NRDP1; MECHANISMS; EXPRESSION; MIGRATION; STROKE; ISCHEMIA/REPERFUSION;

D O I：

10.3389/fncel.2017.00293

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Neuregulin receptor degradation protein-1 (Nrdp1) is an E3 ubiquitin ligase that targets proteins for degradation and regulates cell growth, apoptosis and oxidative stress in various cell types. We have previously shown that Nrdp1 is implicated in ischemic cardiomyocyte death. In this study, we investigated the change of Nrdp1 expression in ischemic neurons and its role in ischemic neuronal injury. Primary rat cerebral cortical neurons and pheochromocytoma (PC12) cells were infected with adenoviral constructs expressing Nrdp1 gene or its siRNA before exposing to oxygen-glucose deprivation (OGD) treatment. Our data showed that Nrdp1 was upregulated in ischemic brain tissue 3 h after middle cerebral artery occlusion (MCAO) and in OGD-treated neurons. Of note, Nrdp1 overexpression by Ad-Nrdp1 enhanced OGD-induced neuron apoptosis, while knockdown of Nrdp1 with siRNA attenuated this effect, implicating a role of Nrdp1 in ischemic neuron injury. Moreover, Nrdp1 upregulation is accompanied by increased protein ubiquitylation and decreased protein levels of ubiquitin-specific protease 8 (USP8) in OGD-treated neurons, which led to a suppressed interaction between USP8 and HIF-1 alpha and subsequently a reduction in HIF-1 alpha protein accumulation in neurons under OGD conditions. In conclusion, our data support an important role of Nrdp1 upregulation in ischemic neuronal death, and suppressing the interaction between USP8 and HIF-1 alpha and consequently the hypoxic adaptive response of neurons may account for this detrimental effect.

引用

页数：10